|
Inhibition of human cytochrome P450 3A4
|
None
|
550.0
nM
|
|
Journal : J. Med. Chem.
Title : Comparison of in vitro P-glycoprotein screening assays: recommendations for their use in drug discovery.
Year : 2003
Volume : 46
Issue : 9
First Page : 1716
Last Page : 1725
Authors : Schwab D, Fischer H, Tabatabaei A, Poli S, Huwyler J.
Abstract : The ATP-dependent drug efflux pump P-glycoprotein (P-gp) affects the absorption and disposition of many compounds. P-gp may also play role in clinically significant drug-drug interactions. Therefore, it is important to find potential substrates or inhibitors of P-gp early in the drug discovery process. To identify compounds that interact with this transporter, several P-gp assays were validated and compared by testing a set of 28 reference compounds, including inhibitors of cytochrome P450 3A4 (CYP3A4). The assays included in silico predictions, inhibition assays (based on cellular uptake of rhodamine-123 or calcein AM), and functional assays (ATPase activity assay and transcellular transport assay, the latter for a subset of compounds). In addition, species differences were studied in an indirect fluorescence indicator screening assay and test systems expressing porcine, mouse, or human P-gp. Our results suggest that several P-gp assays should be used in combination to classify compounds as substrates or inhibitors of P-gp. Recommendations are given on screening strategies which can be applied to different phases of the drug discovery and development process.
|
Compound was tested for inhibitory activity against HIV-1 protease
|
None
|
530.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structure-based design and synthesis of HIV-1 protease inhibitors employing beta-D-mannopyranoside scaffolds.
Year : 2002
Volume : 12
Issue : 13
First Page : 1763
Last Page : 1766
Authors : Murphy PV, O'Brien JL, Gorey-Feret LJ, Smith AB.
Abstract : A preliminary account on the structure-based design, synthesis and evaluation of peptidomimetic inhibitors of HIV-1 protease containing beta-D-mannopyranoside scaffolds is given. The compounds prepared had IC(50) values in the micromolar range. The results provide a platform for the development of more potent carbohydrate-based inhibitors of HIV-1 and other aspartic proteases.
|
Antiviral activity against PI resistant virus EP13 was determined in MT-4 cell line
|
Homo sapiens
|
450.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel arylsulfonamides possessing sub-picomolar HIV protease activities and potent anti-HIV activity against wild-type and drug-resistant viral strains.
Year : 2004
Volume : 14
Issue : 4
First Page : 959
Last Page : 963
Authors : Miller JF, Furfine ES, Hanlon MH, Hazen RJ, Ray JA, Robinson L, Samano V, Spaltenstein A.
Abstract : A novel series of P1' chain-extended arylsufonamides was synthesized and evaluated for wild-type HIV protease inhibitory activity and in vitro antiviral activity against wild type virus and two protease inhibitor-resistant mutant viruses. All of the compounds showed dramatic increases in enzyme activity as compared to the currently marketed HIV protease inhibitors amprenavir, indinavir, and nelfinavir. In addition, significant improvements in antiviral potencies against wild type and the two mutant viruses were also realized.
|
Antiviral activity against wild-type HIV virus (HXB2) was determined in MT-4 cell line
|
Homo sapiens
|
320.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel arylsulfonamides possessing sub-picomolar HIV protease activities and potent anti-HIV activity against wild-type and drug-resistant viral strains.
Year : 2004
Volume : 14
Issue : 4
First Page : 959
Last Page : 963
Authors : Miller JF, Furfine ES, Hanlon MH, Hazen RJ, Ray JA, Robinson L, Samano V, Spaltenstein A.
Abstract : A novel series of P1' chain-extended arylsufonamides was synthesized and evaluated for wild-type HIV protease inhibitory activity and in vitro antiviral activity against wild type virus and two protease inhibitor-resistant mutant viruses. All of the compounds showed dramatic increases in enzyme activity as compared to the currently marketed HIV protease inhibitors amprenavir, indinavir, and nelfinavir. In addition, significant improvements in antiviral potencies against wild type and the two mutant viruses were also realized.
|
Compound was evaluated for its antiviral inhibition in MT-4 cell culture
|
Homo sapiens
|
50.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel inhibitors of HIV protease: design, synthesis and biological evaluation of picomolar inhibitors containing cyclic P1/P2 scaffolds.
Year : 2000
Volume : 10
Issue : 11
First Page : 1159
Last Page : 1162
Authors : Spaltenstein A, Almond MR, Bock WJ, Cleary DG, Furfine ES, Hazen RJ, Kazmierski WM, Salituro FG, Tung RD, Wright LL.
Abstract : A novel series of HIV protease inhibitors containing cyclic P1/P2 scaffolds has been synthesized and evaluated for biological activity. The trans 3,5-dibenzyl-2-oxo pyrrolidinone ring system resulted in a 50 pM enzyme inhibitor against HIV protease in vitro when combined with an indanolamine derived P'-backbone. This compound also shows comparable activity to currently marketed drugs in the MT-4 cell-based antiviral assay.
|
Inhibition of P-glycoprotein using calcein-AM assay transfected in porcine PBCEC
|
None
|
350.0
nM
|
|
Journal : J. Med. Chem.
Title : Comparison of in vitro P-glycoprotein screening assays: recommendations for their use in drug discovery.
Year : 2003
Volume : 46
Issue : 9
First Page : 1716
Last Page : 1725
Authors : Schwab D, Fischer H, Tabatabaei A, Poli S, Huwyler J.
Abstract : The ATP-dependent drug efflux pump P-glycoprotein (P-gp) affects the absorption and disposition of many compounds. P-gp may also play role in clinically significant drug-drug interactions. Therefore, it is important to find potential substrates or inhibitors of P-gp early in the drug discovery process. To identify compounds that interact with this transporter, several P-gp assays were validated and compared by testing a set of 28 reference compounds, including inhibitors of cytochrome P450 3A4 (CYP3A4). The assays included in silico predictions, inhibition assays (based on cellular uptake of rhodamine-123 or calcein AM), and functional assays (ATPase activity assay and transcellular transport assay, the latter for a subset of compounds). In addition, species differences were studied in an indirect fluorescence indicator screening assay and test systems expressing porcine, mouse, or human P-gp. Our results suggest that several P-gp assays should be used in combination to classify compounds as substrates or inhibitors of P-gp. Recommendations are given on screening strategies which can be applied to different phases of the drug discovery and development process.
|
Inhibition of P-gp was determined using rhodamine-assay in human CaCo-2 cells
|
None
|
30.0
%
|
|
Journal : J. Med. Chem.
Title : Comparison of in vitro P-glycoprotein screening assays: recommendations for their use in drug discovery.
Year : 2003
Volume : 46
Issue : 9
First Page : 1716
Last Page : 1725
Authors : Schwab D, Fischer H, Tabatabaei A, Poli S, Huwyler J.
Abstract : The ATP-dependent drug efflux pump P-glycoprotein (P-gp) affects the absorption and disposition of many compounds. P-gp may also play role in clinically significant drug-drug interactions. Therefore, it is important to find potential substrates or inhibitors of P-gp early in the drug discovery process. To identify compounds that interact with this transporter, several P-gp assays were validated and compared by testing a set of 28 reference compounds, including inhibitors of cytochrome P450 3A4 (CYP3A4). The assays included in silico predictions, inhibition assays (based on cellular uptake of rhodamine-123 or calcein AM), and functional assays (ATPase activity assay and transcellular transport assay, the latter for a subset of compounds). In addition, species differences were studied in an indirect fluorescence indicator screening assay and test systems expressing porcine, mouse, or human P-gp. Our results suggest that several P-gp assays should be used in combination to classify compounds as substrates or inhibitors of P-gp. Recommendations are given on screening strategies which can be applied to different phases of the drug discovery and development process.
|
Inhibition of HIV protease
|
Human immunodeficiency virus 1
|
0.01
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel inhibitors of HIV protease: design, synthesis and biological evaluation of picomolar inhibitors containing cyclic P1/P2 scaffolds.
Year : 2000
Volume : 10
Issue : 11
First Page : 1159
Last Page : 1162
Authors : Spaltenstein A, Almond MR, Bock WJ, Cleary DG, Furfine ES, Hazen RJ, Kazmierski WM, Salituro FG, Tung RD, Wright LL.
Abstract : A novel series of HIV protease inhibitors containing cyclic P1/P2 scaffolds has been synthesized and evaluated for biological activity. The trans 3,5-dibenzyl-2-oxo pyrrolidinone ring system resulted in a 50 pM enzyme inhibitor against HIV protease in vitro when combined with an indanolamine derived P'-backbone. This compound also shows comparable activity to currently marketed drugs in the MT-4 cell-based antiviral assay.
|
Inhibition constant against HIV-1 Protease
|
Human immunodeficiency virus 1
|
0.54
nM
|
|
Journal : J. Med. Chem.
Title : Relationships between structure and interaction kinetics for HIV-1 protease inhibitors.
Year : 2002
Volume : 45
Issue : 25
First Page : 5430
Last Page : 5439
Authors : Markgren PO, Schaal W, Hämäläinen M, Karlén A, Hallberg A, Samuelsson B, Danielson UH.
Abstract : The interaction between HIV-1 protease and 58 structurally diverse transition-state analogue inhibitors has been analyzed by a surface plasmon resonance based biosensor. Association and dissociation rate constants and affinities were determined and displayed as k(on)-k(off)-K(D) maps. It was shown that different classes of inhibitors fall into distinct clusters in these maps. Significant changes in association and dissociation rates were found as a result of modifying the P1/P1' or P2/P2' side chains of a linear lead compound. Similarly, cyclic urea and cyclic sulfamide inhibitors displayed different kinetic features and the affinities of both classes of cyclic compounds were limited by fast dissociation rates. These results confirm that association and dissociation rates are important features of drug-target interactions and indicate that optimization of inhibitor efficacy may be guided by aiming for high association and low dissociation rates rather than high affinity alone. The present approach thus provides a new tool for structure-interaction kinetic analysis and drug discovery.
|
Inhibitory concentration against HIV-1 protease
|
Human immunodeficiency virus 1
|
0.23
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of potent C(2)-symmetric diol-based HIV-1 protease inhibitors: effects of fluoro substitution.
Year : 2001
Volume : 44
Issue : 19
First Page : 3083
Last Page : 3091
Authors : Pyring D, Lindberg J, Rosenquist A, Zuccarello G, Kvarnström I, Zhang H, Vrang L, Unge T, Classon B, Hallberg A, Samuelsson B.
Abstract : Implementation of derivatized carbohydrates as C(2)-symmetric HIV-1 protease inhibitors has previously been reported. With the objective of improving the anti-HIV activity of such compounds, we synthesized a series of fluoro substituted P1/P1' analogues. These compounds were evaluated for antiviral activity toward both wild type and mutant virus. The potency of the analogues in blocking HIV-1 protease was moderate, with K(i) values ranging from 1 to 7 nM. Nonetheless, compared to the parent nonfluorous inhibitors, a majority of the compounds exhibited improved antiviral activity, for example the 3-fluorobenzyl derivative 9b, which had a K(i) value of 7.13 nM and displayed one of the most powerful antiviral activities in the cellular assay of the series. Our results strongly suggest that fluoro substitution can substantially improve antiviral activity. The X-ray crystal structures of two of the fluoro substituted inhibitors (9a and 9f) cocrystallized with HIV-1 protease are discussed.
|
Inhibition of HIV-1 Protease activity
|
Human immunodeficiency virus 1
|
0.17
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel arylsulfonamides possessing sub-picomolar HIV protease activities and potent anti-HIV activity against wild-type and drug-resistant viral strains.
Year : 2004
Volume : 14
Issue : 4
First Page : 959
Last Page : 963
Authors : Miller JF, Furfine ES, Hanlon MH, Hazen RJ, Ray JA, Robinson L, Samano V, Spaltenstein A.
Abstract : A novel series of P1' chain-extended arylsufonamides was synthesized and evaluated for wild-type HIV protease inhibitory activity and in vitro antiviral activity against wild type virus and two protease inhibitor-resistant mutant viruses. All of the compounds showed dramatic increases in enzyme activity as compared to the currently marketed HIV protease inhibitors amprenavir, indinavir, and nelfinavir. In addition, significant improvements in antiviral potencies against wild type and the two mutant viruses were also realized.
|
Binding affinity against HIV-protease inhibitor.
|
Human immunodeficiency virus
|
2.0
nM
|
|
Journal : J. Med. Chem.
Title : Protease inhibitors: current status and future prospects.
Year : 2000
Volume : 43
Issue : 3
First Page : 305
Last Page : 341
Authors : Leung D, Abbenante G, Fairlie DP.
|
Equilibrium constant for the interaction between inhibitor and HIV-1 Protease
|
Human immunodeficiency virus 1
|
1.64
nM
|
|
Journal : J. Med. Chem.
Title : Relationships between structure and interaction kinetics for HIV-1 protease inhibitors.
Year : 2002
Volume : 45
Issue : 25
First Page : 5430
Last Page : 5439
Authors : Markgren PO, Schaal W, Hämäläinen M, Karlén A, Hallberg A, Samuelsson B, Danielson UH.
Abstract : The interaction between HIV-1 protease and 58 structurally diverse transition-state analogue inhibitors has been analyzed by a surface plasmon resonance based biosensor. Association and dissociation rate constants and affinities were determined and displayed as k(on)-k(off)-K(D) maps. It was shown that different classes of inhibitors fall into distinct clusters in these maps. Significant changes in association and dissociation rates were found as a result of modifying the P1/P1' or P2/P2' side chains of a linear lead compound. Similarly, cyclic urea and cyclic sulfamide inhibitors displayed different kinetic features and the affinities of both classes of cyclic compounds were limited by fast dissociation rates. These results confirm that association and dissociation rates are important features of drug-target interactions and indicate that optimization of inhibitor efficacy may be guided by aiming for high association and low dissociation rates rather than high affinity alone. The present approach thus provides a new tool for structure-interaction kinetic analysis and drug discovery.
|
Dissociation constant obtained by inhibition of Wild-type protease
|
None
|
0.14
nM
|
|
Journal : J. Med. Chem.
Title : Identification of MK-944a: a second clinical candidate from the hydroxylaminepentanamide isostere series of HIV protease inhibitors.
Year : 2000
Volume : 43
Issue : 18
First Page : 3386
Last Page : 3399
Authors : Dorsey BD, McDonough C, McDaniel SL, Levin RB, Newton CL, Hoffman JM, Darke PL, Zugay-Murphy JA, Emini EA, Schleif WA, Olsen DB, Stahlhut MW, Rutkowski CA, Kuo LC, Lin JH, Chen IW, Michelson SR, Holloway MK, Huff JR, Vacca JP.
Abstract : Recent results from human clinical trials have established the critical role of HIV protease inhibitors in the treatment of acquired immune-deficiency syndrome (AIDS). However, the emergence of viral resistance, demanding treatment protocols, and adverse side effects have exposed the urgent need for a second generation of HIV protease inhibitors. The continued exploration of our hydroxylaminepentanamide (HAPA) transition-state isostere series of HIV protease inhibitors, which initially resulted in the identification of Crixivan (indinavir sulfate, MK-639, L-735,524), has now yielded MK-944a (L-756,423). This compound is potent, is selective, and competitively inhibits HIV-1 PR with a K(i) value of 0.049 nM. It stops the spread of the HIV(IIIb)-infected MT4 lymphoid cells at 25.0-50.0 nM, even in the presence of alpha(1) acid glycoprotein, human serum albumin, normal human serum, or fetal bovine serum. MK-944a has a longer half-life in several animal models (rats, dogs, and monkeys) than indinavir sulfate and is currently in advanced human clinical trials.
|
Dissociation constant obtained by inhibition of mutant HIV-protease (A-44)
|
None
|
16.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification of MK-944a: a second clinical candidate from the hydroxylaminepentanamide isostere series of HIV protease inhibitors.
Year : 2000
Volume : 43
Issue : 18
First Page : 3386
Last Page : 3399
Authors : Dorsey BD, McDonough C, McDaniel SL, Levin RB, Newton CL, Hoffman JM, Darke PL, Zugay-Murphy JA, Emini EA, Schleif WA, Olsen DB, Stahlhut MW, Rutkowski CA, Kuo LC, Lin JH, Chen IW, Michelson SR, Holloway MK, Huff JR, Vacca JP.
Abstract : Recent results from human clinical trials have established the critical role of HIV protease inhibitors in the treatment of acquired immune-deficiency syndrome (AIDS). However, the emergence of viral resistance, demanding treatment protocols, and adverse side effects have exposed the urgent need for a second generation of HIV protease inhibitors. The continued exploration of our hydroxylaminepentanamide (HAPA) transition-state isostere series of HIV protease inhibitors, which initially resulted in the identification of Crixivan (indinavir sulfate, MK-639, L-735,524), has now yielded MK-944a (L-756,423). This compound is potent, is selective, and competitively inhibits HIV-1 PR with a K(i) value of 0.049 nM. It stops the spread of the HIV(IIIb)-infected MT4 lymphoid cells at 25.0-50.0 nM, even in the presence of alpha(1) acid glycoprotein, human serum albumin, normal human serum, or fetal bovine serum. MK-944a has a longer half-life in several animal models (rats, dogs, and monkeys) than indinavir sulfate and is currently in advanced human clinical trials.
|
Dissociation constant obtained by inhibition of mutant HIV-protease (K-60)
|
None
|
33.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification of MK-944a: a second clinical candidate from the hydroxylaminepentanamide isostere series of HIV protease inhibitors.
Year : 2000
Volume : 43
Issue : 18
First Page : 3386
Last Page : 3399
Authors : Dorsey BD, McDonough C, McDaniel SL, Levin RB, Newton CL, Hoffman JM, Darke PL, Zugay-Murphy JA, Emini EA, Schleif WA, Olsen DB, Stahlhut MW, Rutkowski CA, Kuo LC, Lin JH, Chen IW, Michelson SR, Holloway MK, Huff JR, Vacca JP.
Abstract : Recent results from human clinical trials have established the critical role of HIV protease inhibitors in the treatment of acquired immune-deficiency syndrome (AIDS). However, the emergence of viral resistance, demanding treatment protocols, and adverse side effects have exposed the urgent need for a second generation of HIV protease inhibitors. The continued exploration of our hydroxylaminepentanamide (HAPA) transition-state isostere series of HIV protease inhibitors, which initially resulted in the identification of Crixivan (indinavir sulfate, MK-639, L-735,524), has now yielded MK-944a (L-756,423). This compound is potent, is selective, and competitively inhibits HIV-1 PR with a K(i) value of 0.049 nM. It stops the spread of the HIV(IIIb)-infected MT4 lymphoid cells at 25.0-50.0 nM, even in the presence of alpha(1) acid glycoprotein, human serum albumin, normal human serum, or fetal bovine serum. MK-944a has a longer half-life in several animal models (rats, dogs, and monkeys) than indinavir sulfate and is currently in advanced human clinical trials.
|
Dissociation constant obtained by inhibition of mutant HIV-protease (V-18)
|
None
|
27.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification of MK-944a: a second clinical candidate from the hydroxylaminepentanamide isostere series of HIV protease inhibitors.
Year : 2000
Volume : 43
Issue : 18
First Page : 3386
Last Page : 3399
Authors : Dorsey BD, McDonough C, McDaniel SL, Levin RB, Newton CL, Hoffman JM, Darke PL, Zugay-Murphy JA, Emini EA, Schleif WA, Olsen DB, Stahlhut MW, Rutkowski CA, Kuo LC, Lin JH, Chen IW, Michelson SR, Holloway MK, Huff JR, Vacca JP.
Abstract : Recent results from human clinical trials have established the critical role of HIV protease inhibitors in the treatment of acquired immune-deficiency syndrome (AIDS). However, the emergence of viral resistance, demanding treatment protocols, and adverse side effects have exposed the urgent need for a second generation of HIV protease inhibitors. The continued exploration of our hydroxylaminepentanamide (HAPA) transition-state isostere series of HIV protease inhibitors, which initially resulted in the identification of Crixivan (indinavir sulfate, MK-639, L-735,524), has now yielded MK-944a (L-756,423). This compound is potent, is selective, and competitively inhibits HIV-1 PR with a K(i) value of 0.049 nM. It stops the spread of the HIV(IIIb)-infected MT4 lymphoid cells at 25.0-50.0 nM, even in the presence of alpha(1) acid glycoprotein, human serum albumin, normal human serum, or fetal bovine serum. MK-944a has a longer half-life in several animal models (rats, dogs, and monkeys) than indinavir sulfate and is currently in advanced human clinical trials.
|
Binding affinity for human immunodeficiency virus type 1 protease
|
Human immunodeficiency virus 1
|
1.64
nM
|
|
Journal : J. Med. Chem.
Title : Improved structure-activity relationship analysis of HIV-1 protease inhibitors using interaction kinetic data.
Year : 2004
Volume : 47
Issue : 24
First Page : 5953
Last Page : 5961
Authors : Shuman CF, Vrang L, Danielson UH.
Abstract : Despite the availability of large amounts of data for HIV-protease inhibitors and their effectiveness with wild type and resistant enzyme, there is limited knowledge about how this and other information can be systematically applied to the development of new antiviral compounds. To identify in vitro parameters that correlate with the efficacy of HIV inhibitors in cell culture, the relationships between inhibition, interaction kinetic, and cell culture parameters for HIV-1 protease inhibitors were analyzed. Correlation, cluster, and principal component analysis of data for 37 cyclic and linear compounds revealed that the affinities (K(D)) determined from SPR-biosensor binding studies correlated better to cell culture efficacy (ED(50)) than that of the inhibition constants (K(i)), indicating that the conventional use of K(i) values for structure-activity relationship analysis of HIV-1 inhibitors should be seriously reconsidered. The association and dissociation kinetic rate constants (k(on) and k(off)) alone showed weak correlations with ED(50) values. However, ED(50) values were most related to the free enzyme concentration in the viral particle ([E]), calculated from the rate constants and the total enzyme concentration in a viral particle. A structure-activity relationship analysis of the current data set was found to be valid for all classes of compounds analyzed. In summary, use of affinity, based on interaction kinetic rate constants, rather than inhibition constants, and theoretical consideration of the physiological conditions in the virus particle provide improved structure-activity relationship analysis of HIV-1 protease inhibitors.
|
Inhibition constant for human immunodeficiency virus type 1 protease
|
Human immunodeficiency virus 1
|
0.54
nM
|
|
Journal : J. Med. Chem.
Title : Improved structure-activity relationship analysis of HIV-1 protease inhibitors using interaction kinetic data.
Year : 2004
Volume : 47
Issue : 24
First Page : 5953
Last Page : 5961
Authors : Shuman CF, Vrang L, Danielson UH.
Abstract : Despite the availability of large amounts of data for HIV-protease inhibitors and their effectiveness with wild type and resistant enzyme, there is limited knowledge about how this and other information can be systematically applied to the development of new antiviral compounds. To identify in vitro parameters that correlate with the efficacy of HIV inhibitors in cell culture, the relationships between inhibition, interaction kinetic, and cell culture parameters for HIV-1 protease inhibitors were analyzed. Correlation, cluster, and principal component analysis of data for 37 cyclic and linear compounds revealed that the affinities (K(D)) determined from SPR-biosensor binding studies correlated better to cell culture efficacy (ED(50)) than that of the inhibition constants (K(i)), indicating that the conventional use of K(i) values for structure-activity relationship analysis of HIV-1 inhibitors should be seriously reconsidered. The association and dissociation kinetic rate constants (k(on) and k(off)) alone showed weak correlations with ED(50) values. However, ED(50) values were most related to the free enzyme concentration in the viral particle ([E]), calculated from the rate constants and the total enzyme concentration in a viral particle. A structure-activity relationship analysis of the current data set was found to be valid for all classes of compounds analyzed. In summary, use of affinity, based on interaction kinetic rate constants, rather than inhibition constants, and theoretical consideration of the physiological conditions in the virus particle provide improved structure-activity relationship analysis of HIV-1 protease inhibitors.
|
Inhibitory concentration against wild type Human immuno deficiency virus (EP13) was determined in an MT-4 cell line
|
Human immunodeficiency virus 1
|
450.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel P1 chain-extended HIV protease inhibitors possessing potent anti-HIV activity and remarkable inverse antiviral resistance profiles.
Year : 2005
Volume : 15
Issue : 15
First Page : 3496
Last Page : 3500
Authors : Miller JF, Brieger M, Furfine ES, Hazen RJ, Kaldor I, Reynolds D, Sherrill RG, Spaltenstein A.
Abstract : A novel series of tyrosine-derived HIV protease inhibitors was synthesized and evaluated for in vitro antiviral activity against wild-type virus and two protease inhibitor-resistant viruses. All of the compounds had wild-type antiviral activities that were similar to or greater than several currently marketed HIV protease inhibitors. In addition, a number of compounds in this series were more potent against the drug-resistant mutant viruses than they were against wild-type virus.
|
Inhibitory concentration against wild type Human immuno deficiency virus (HXB2) was determined in an MT-4 cell line
|
Human immunodeficiency virus 1
|
320.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel P1 chain-extended HIV protease inhibitors possessing potent anti-HIV activity and remarkable inverse antiviral resistance profiles.
Year : 2005
Volume : 15
Issue : 15
First Page : 3496
Last Page : 3500
Authors : Miller JF, Brieger M, Furfine ES, Hazen RJ, Kaldor I, Reynolds D, Sherrill RG, Spaltenstein A.
Abstract : A novel series of tyrosine-derived HIV protease inhibitors was synthesized and evaluated for in vitro antiviral activity against wild-type virus and two protease inhibitor-resistant viruses. All of the compounds had wild-type antiviral activities that were similar to or greater than several currently marketed HIV protease inhibitors. In addition, a number of compounds in this series were more potent against the drug-resistant mutant viruses than they were against wild-type virus.
|
Antiviral activity against HIV1 HXB2 in MT4 cells
|
None
|
320.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Ultra-potent P1 modified arylsulfonamide HIV protease inhibitors: the discovery of GW0385.
Year : 2006
Volume : 16
Issue : 7
First Page : 1788
Last Page : 1794
Authors : Miller JF, Andrews CW, Brieger M, Furfine ES, Hale MR, Hanlon MH, Hazen RJ, Kaldor I, McLean EW, Reynolds D, Sammond DM, Spaltenstein A, Tung R, Turner EM, Xu RX, Sherrill RG.
Abstract : A novel series of P1 modified HIV protease inhibitors was synthesized and evaluated for in vitro antiviral activity against wild-type virus and protease inhibitor-resistant viruses. Optimization of the P1 moiety resulted in compounds with femtomolar enzyme activities and cellular antiviral activities in the low nanomolar range culminating in the identification of clinical candidate GW0385.
|
Antiviral activity against HIV1 EP13 in MT4 cells
|
None
|
450.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Ultra-potent P1 modified arylsulfonamide HIV protease inhibitors: the discovery of GW0385.
Year : 2006
Volume : 16
Issue : 7
First Page : 1788
Last Page : 1794
Authors : Miller JF, Andrews CW, Brieger M, Furfine ES, Hale MR, Hanlon MH, Hazen RJ, Kaldor I, McLean EW, Reynolds D, Sammond DM, Spaltenstein A, Tung R, Turner EM, Xu RX, Sherrill RG.
Abstract : A novel series of P1 modified HIV protease inhibitors was synthesized and evaluated for in vitro antiviral activity against wild-type virus and protease inhibitor-resistant viruses. Optimization of the P1 moiety resulted in compounds with femtomolar enzyme activities and cellular antiviral activities in the low nanomolar range culminating in the identification of clinical candidate GW0385.
|
Antiviral activity against HIV1 LAI isolate in human MT2 cells
|
Human immunodeficiency virus 1
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-based design of novel HIV-1 protease inhibitors to combat drug resistance.
Year : 2006
Volume : 49
Issue : 17
First Page : 5252
Last Page : 5261
Authors : Ghosh AK, Sridhar PR, Leshchenko S, Hussain AK, Li J, Kovalevsky AY, Walters DE, Wedekind JE, Grum-Tokars V, Das D, Koh Y, Maeda K, Gatanaga H, Weber IT, Mitsuya H.
Abstract : Structure-based design and synthesis of novel HIV protease inhibitors are described. The inhibitors are designed specifically to interact with the backbone of HIV protease active site to combat drug resistance. Inhibitor 3 has exhibited exceedingly potent enzyme inhibitory and antiviral potency. Furthermore, this inhibitor maintains impressive potency against a wide spectrum of HIV including a variety of multi-PI-resistant clinical strains. The inhibitors incorporated a stereochemically defined 5-hexahydrocyclopenta[b]furanyl urethane as the P2-ligand into the (R)-(hydroxyethylamino)sulfonamide isostere. Optically active (3aS,5R,6aR)-5-hydroxy-hexahydrocyclopenta[b]furan was prepared by an enzymatic asymmetrization of meso-diacetate with acetyl cholinesterase, radical cyclization, and Lewis acid-catalyzed anomeric reduction as the key steps. A protein-ligand X-ray crystal structure of inhibitor 3-bound HIV-1 protease (1.35 A resolution) revealed extensive interactions in the HIV protease active site including strong hydrogen bonding interactions with the backbone. This design strategy may lead to novel inhibitors that can combat drug resistance.
|
Antiviral activity against HIV1 LAI isolate in human PHA-PBMC cells
|
Human immunodeficiency virus 1
|
14.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-based design of novel HIV-1 protease inhibitors to combat drug resistance.
Year : 2006
Volume : 49
Issue : 17
First Page : 5252
Last Page : 5261
Authors : Ghosh AK, Sridhar PR, Leshchenko S, Hussain AK, Li J, Kovalevsky AY, Walters DE, Wedekind JE, Grum-Tokars V, Das D, Koh Y, Maeda K, Gatanaga H, Weber IT, Mitsuya H.
Abstract : Structure-based design and synthesis of novel HIV protease inhibitors are described. The inhibitors are designed specifically to interact with the backbone of HIV protease active site to combat drug resistance. Inhibitor 3 has exhibited exceedingly potent enzyme inhibitory and antiviral potency. Furthermore, this inhibitor maintains impressive potency against a wide spectrum of HIV including a variety of multi-PI-resistant clinical strains. The inhibitors incorporated a stereochemically defined 5-hexahydrocyclopenta[b]furanyl urethane as the P2-ligand into the (R)-(hydroxyethylamino)sulfonamide isostere. Optically active (3aS,5R,6aR)-5-hydroxy-hexahydrocyclopenta[b]furan was prepared by an enzymatic asymmetrization of meso-diacetate with acetyl cholinesterase, radical cyclization, and Lewis acid-catalyzed anomeric reduction as the key steps. A protein-ligand X-ray crystal structure of inhibitor 3-bound HIV-1 protease (1.35 A resolution) revealed extensive interactions in the HIV protease active site including strong hydrogen bonding interactions with the backbone. This design strategy may lead to novel inhibitors that can combat drug resistance.
|
Antiviral activity against HIV1 BA-L isolate in human PHA-PBMC cells
|
Human immunodeficiency virus 1
|
7.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-based design of novel HIV-1 protease inhibitors to combat drug resistance.
Year : 2006
Volume : 49
Issue : 17
First Page : 5252
Last Page : 5261
Authors : Ghosh AK, Sridhar PR, Leshchenko S, Hussain AK, Li J, Kovalevsky AY, Walters DE, Wedekind JE, Grum-Tokars V, Das D, Koh Y, Maeda K, Gatanaga H, Weber IT, Mitsuya H.
Abstract : Structure-based design and synthesis of novel HIV protease inhibitors are described. The inhibitors are designed specifically to interact with the backbone of HIV protease active site to combat drug resistance. Inhibitor 3 has exhibited exceedingly potent enzyme inhibitory and antiviral potency. Furthermore, this inhibitor maintains impressive potency against a wide spectrum of HIV including a variety of multi-PI-resistant clinical strains. The inhibitors incorporated a stereochemically defined 5-hexahydrocyclopenta[b]furanyl urethane as the P2-ligand into the (R)-(hydroxyethylamino)sulfonamide isostere. Optically active (3aS,5R,6aR)-5-hydroxy-hexahydrocyclopenta[b]furan was prepared by an enzymatic asymmetrization of meso-diacetate with acetyl cholinesterase, radical cyclization, and Lewis acid-catalyzed anomeric reduction as the key steps. A protein-ligand X-ray crystal structure of inhibitor 3-bound HIV-1 protease (1.35 A resolution) revealed extensive interactions in the HIV protease active site including strong hydrogen bonding interactions with the backbone. This design strategy may lead to novel inhibitors that can combat drug resistance.
|
Antiviral activity against HIV2 EHO isolate in human MT2 cells
|
Human immunodeficiency virus 2
|
20.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-based design of novel HIV-1 protease inhibitors to combat drug resistance.
Year : 2006
Volume : 49
Issue : 17
First Page : 5252
Last Page : 5261
Authors : Ghosh AK, Sridhar PR, Leshchenko S, Hussain AK, Li J, Kovalevsky AY, Walters DE, Wedekind JE, Grum-Tokars V, Das D, Koh Y, Maeda K, Gatanaga H, Weber IT, Mitsuya H.
Abstract : Structure-based design and synthesis of novel HIV protease inhibitors are described. The inhibitors are designed specifically to interact with the backbone of HIV protease active site to combat drug resistance. Inhibitor 3 has exhibited exceedingly potent enzyme inhibitory and antiviral potency. Furthermore, this inhibitor maintains impressive potency against a wide spectrum of HIV including a variety of multi-PI-resistant clinical strains. The inhibitors incorporated a stereochemically defined 5-hexahydrocyclopenta[b]furanyl urethane as the P2-ligand into the (R)-(hydroxyethylamino)sulfonamide isostere. Optically active (3aS,5R,6aR)-5-hydroxy-hexahydrocyclopenta[b]furan was prepared by an enzymatic asymmetrization of meso-diacetate with acetyl cholinesterase, radical cyclization, and Lewis acid-catalyzed anomeric reduction as the key steps. A protein-ligand X-ray crystal structure of inhibitor 3-bound HIV-1 protease (1.35 A resolution) revealed extensive interactions in the HIV protease active site including strong hydrogen bonding interactions with the backbone. This design strategy may lead to novel inhibitors that can combat drug resistance.
|
Antiviral activity against multi drug-resistant HIV1 ET variant in human PHA-PBMC cells
|
Human immunodeficiency virus 1
|
32.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-based design of novel HIV-1 protease inhibitors to combat drug resistance.
Year : 2006
Volume : 49
Issue : 17
First Page : 5252
Last Page : 5261
Authors : Ghosh AK, Sridhar PR, Leshchenko S, Hussain AK, Li J, Kovalevsky AY, Walters DE, Wedekind JE, Grum-Tokars V, Das D, Koh Y, Maeda K, Gatanaga H, Weber IT, Mitsuya H.
Abstract : Structure-based design and synthesis of novel HIV protease inhibitors are described. The inhibitors are designed specifically to interact with the backbone of HIV protease active site to combat drug resistance. Inhibitor 3 has exhibited exceedingly potent enzyme inhibitory and antiviral potency. Furthermore, this inhibitor maintains impressive potency against a wide spectrum of HIV including a variety of multi-PI-resistant clinical strains. The inhibitors incorporated a stereochemically defined 5-hexahydrocyclopenta[b]furanyl urethane as the P2-ligand into the (R)-(hydroxyethylamino)sulfonamide isostere. Optically active (3aS,5R,6aR)-5-hydroxy-hexahydrocyclopenta[b]furan was prepared by an enzymatic asymmetrization of meso-diacetate with acetyl cholinesterase, radical cyclization, and Lewis acid-catalyzed anomeric reduction as the key steps. A protein-ligand X-ray crystal structure of inhibitor 3-bound HIV-1 protease (1.35 A resolution) revealed extensive interactions in the HIV protease active site including strong hydrogen bonding interactions with the backbone. This design strategy may lead to novel inhibitors that can combat drug resistance.
|
Antiviral activity against multi drug-resistant HIV1 C variant in human PHA-PBMC cells
|
Human immunodeficiency virus 1
|
310.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-based design of novel HIV-1 protease inhibitors to combat drug resistance.
Year : 2006
Volume : 49
Issue : 17
First Page : 5252
Last Page : 5261
Authors : Ghosh AK, Sridhar PR, Leshchenko S, Hussain AK, Li J, Kovalevsky AY, Walters DE, Wedekind JE, Grum-Tokars V, Das D, Koh Y, Maeda K, Gatanaga H, Weber IT, Mitsuya H.
Abstract : Structure-based design and synthesis of novel HIV protease inhibitors are described. The inhibitors are designed specifically to interact with the backbone of HIV protease active site to combat drug resistance. Inhibitor 3 has exhibited exceedingly potent enzyme inhibitory and antiviral potency. Furthermore, this inhibitor maintains impressive potency against a wide spectrum of HIV including a variety of multi-PI-resistant clinical strains. The inhibitors incorporated a stereochemically defined 5-hexahydrocyclopenta[b]furanyl urethane as the P2-ligand into the (R)-(hydroxyethylamino)sulfonamide isostere. Optically active (3aS,5R,6aR)-5-hydroxy-hexahydrocyclopenta[b]furan was prepared by an enzymatic asymmetrization of meso-diacetate with acetyl cholinesterase, radical cyclization, and Lewis acid-catalyzed anomeric reduction as the key steps. A protein-ligand X-ray crystal structure of inhibitor 3-bound HIV-1 protease (1.35 A resolution) revealed extensive interactions in the HIV protease active site including strong hydrogen bonding interactions with the backbone. This design strategy may lead to novel inhibitors that can combat drug resistance.
|
Antiviral activity against multi drug-resistant HIV1 G variant in human PHA-PBMC cells
|
Human immunodeficiency virus 1
|
170.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-based design of novel HIV-1 protease inhibitors to combat drug resistance.
Year : 2006
Volume : 49
Issue : 17
First Page : 5252
Last Page : 5261
Authors : Ghosh AK, Sridhar PR, Leshchenko S, Hussain AK, Li J, Kovalevsky AY, Walters DE, Wedekind JE, Grum-Tokars V, Das D, Koh Y, Maeda K, Gatanaga H, Weber IT, Mitsuya H.
Abstract : Structure-based design and synthesis of novel HIV protease inhibitors are described. The inhibitors are designed specifically to interact with the backbone of HIV protease active site to combat drug resistance. Inhibitor 3 has exhibited exceedingly potent enzyme inhibitory and antiviral potency. Furthermore, this inhibitor maintains impressive potency against a wide spectrum of HIV including a variety of multi-PI-resistant clinical strains. The inhibitors incorporated a stereochemically defined 5-hexahydrocyclopenta[b]furanyl urethane as the P2-ligand into the (R)-(hydroxyethylamino)sulfonamide isostere. Optically active (3aS,5R,6aR)-5-hydroxy-hexahydrocyclopenta[b]furan was prepared by an enzymatic asymmetrization of meso-diacetate with acetyl cholinesterase, radical cyclization, and Lewis acid-catalyzed anomeric reduction as the key steps. A protein-ligand X-ray crystal structure of inhibitor 3-bound HIV-1 protease (1.35 A resolution) revealed extensive interactions in the HIV protease active site including strong hydrogen bonding interactions with the backbone. This design strategy may lead to novel inhibitors that can combat drug resistance.
|
Antiviral activity against wild type HIV2 in CBMCs
|
Human immunodeficiency virus 2
|
64.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Natural polymorphisms in the human immunodeficiency virus type 2 protease can accelerate time to development of resistance to protease inhibitors.
Year : 2007
Volume : 51
Issue : 2
First Page : 604
Last Page : 610
Authors : Ntemgwa M, Brenner BG, Oliveira M, Moisi D, Wainberg MA.
Abstract : Human immunodeficiency virus type 2 (HIV-2) contains numerous natural polymorphisms in its protease (PR) gene that are implicated in drug resistance in the case of HIV-1. This study evaluated emergent PR resistance in HIV-2. Three HIV-2 isolates were selected for resistance to amprenavir (APV), nelfinavir (NFV), indinavir (IDV), and tipranavir (TPV) in cell culture. Genotypic analysis determined the time to the appearance of protease inhibitor (PI)-associated mutations compared to HIV-1. Phenotypic drug susceptibility assays were used to determine the levels of drug resistance. Within 10 to 15 weeks of serial passage, three major mutations--I54M, I82F, and L90M--arose in HIV-2 viral cultures exposed to APV, NFV, and IDV, whereas I82L was selected with TPV. After 25 weeks, other cultures had developed I50V and I84V mutations. In contrast, no major PI mutations were selected in HIV-1 over this period except for D30N in the context of NFV selective pressure. The baseline phenotypes of wild-type HIV-2 isolates were in the range observed for HIV-1, except for APV and NFV for which a lower degree of sensitivity was seen. The acquisition of the I54M, I84V, L90M, and L99F mutations resulted in multi-PI-resistant viruses, conferring 10-fold to more than 100-fold resistance. Of note, we observed a 62A/99F mutational motif that conferred high-level resistance to PIs, as well as novel secondary mutations, including 6F, 12A, and 21K. Thus, natural polymorphisms in HIV-2 may facilitate the selection of PI resistance. The increasing incidence of such polymorphisms in drug-naive HIV-1- and HIV-2-infected persons is of concern.
|
Antiviral activity against HIV2 isolate CBL20, CBL23, MVP15132 with 182L mutation in CBMCs
|
Human immunodeficiency virus 2
|
106.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Natural polymorphisms in the human immunodeficiency virus type 2 protease can accelerate time to development of resistance to protease inhibitors.
Year : 2007
Volume : 51
Issue : 2
First Page : 604
Last Page : 610
Authors : Ntemgwa M, Brenner BG, Oliveira M, Moisi D, Wainberg MA.
Abstract : Human immunodeficiency virus type 2 (HIV-2) contains numerous natural polymorphisms in its protease (PR) gene that are implicated in drug resistance in the case of HIV-1. This study evaluated emergent PR resistance in HIV-2. Three HIV-2 isolates were selected for resistance to amprenavir (APV), nelfinavir (NFV), indinavir (IDV), and tipranavir (TPV) in cell culture. Genotypic analysis determined the time to the appearance of protease inhibitor (PI)-associated mutations compared to HIV-1. Phenotypic drug susceptibility assays were used to determine the levels of drug resistance. Within 10 to 15 weeks of serial passage, three major mutations--I54M, I82F, and L90M--arose in HIV-2 viral cultures exposed to APV, NFV, and IDV, whereas I82L was selected with TPV. After 25 weeks, other cultures had developed I50V and I84V mutations. In contrast, no major PI mutations were selected in HIV-1 over this period except for D30N in the context of NFV selective pressure. The baseline phenotypes of wild-type HIV-2 isolates were in the range observed for HIV-1, except for APV and NFV for which a lower degree of sensitivity was seen. The acquisition of the I54M, I84V, L90M, and L99F mutations resulted in multi-PI-resistant viruses, conferring 10-fold to more than 100-fold resistance. Of note, we observed a 62A/99F mutational motif that conferred high-level resistance to PIs, as well as novel secondary mutations, including 6F, 12A, and 21K. Thus, natural polymorphisms in HIV-2 may facilitate the selection of PI resistance. The increasing incidence of such polymorphisms in drug-naive HIV-1- and HIV-2-infected persons is of concern.
|
Antiviral activity against HIV2 isolate CBL20, CBL23, MVP15132 with 182F mutation in CBMCs
|
Human immunodeficiency virus 2
|
244.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Natural polymorphisms in the human immunodeficiency virus type 2 protease can accelerate time to development of resistance to protease inhibitors.
Year : 2007
Volume : 51
Issue : 2
First Page : 604
Last Page : 610
Authors : Ntemgwa M, Brenner BG, Oliveira M, Moisi D, Wainberg MA.
Abstract : Human immunodeficiency virus type 2 (HIV-2) contains numerous natural polymorphisms in its protease (PR) gene that are implicated in drug resistance in the case of HIV-1. This study evaluated emergent PR resistance in HIV-2. Three HIV-2 isolates were selected for resistance to amprenavir (APV), nelfinavir (NFV), indinavir (IDV), and tipranavir (TPV) in cell culture. Genotypic analysis determined the time to the appearance of protease inhibitor (PI)-associated mutations compared to HIV-1. Phenotypic drug susceptibility assays were used to determine the levels of drug resistance. Within 10 to 15 weeks of serial passage, three major mutations--I54M, I82F, and L90M--arose in HIV-2 viral cultures exposed to APV, NFV, and IDV, whereas I82L was selected with TPV. After 25 weeks, other cultures had developed I50V and I84V mutations. In contrast, no major PI mutations were selected in HIV-1 over this period except for D30N in the context of NFV selective pressure. The baseline phenotypes of wild-type HIV-2 isolates were in the range observed for HIV-1, except for APV and NFV for which a lower degree of sensitivity was seen. The acquisition of the I54M, I84V, L90M, and L99F mutations resulted in multi-PI-resistant viruses, conferring 10-fold to more than 100-fold resistance. Of note, we observed a 62A/99F mutational motif that conferred high-level resistance to PIs, as well as novel secondary mutations, including 6F, 12A, and 21K. Thus, natural polymorphisms in HIV-2 may facilitate the selection of PI resistance. The increasing incidence of such polymorphisms in drug-naive HIV-1- and HIV-2-infected persons is of concern.
|
Antiviral activity against HIV2 isolate CBL20, CBL23, MVP15132 with V62A and L99F mutation in CBMCs
|
Human immunodeficiency virus 2
|
961.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Natural polymorphisms in the human immunodeficiency virus type 2 protease can accelerate time to development of resistance to protease inhibitors.
Year : 2007
Volume : 51
Issue : 2
First Page : 604
Last Page : 610
Authors : Ntemgwa M, Brenner BG, Oliveira M, Moisi D, Wainberg MA.
Abstract : Human immunodeficiency virus type 2 (HIV-2) contains numerous natural polymorphisms in its protease (PR) gene that are implicated in drug resistance in the case of HIV-1. This study evaluated emergent PR resistance in HIV-2. Three HIV-2 isolates were selected for resistance to amprenavir (APV), nelfinavir (NFV), indinavir (IDV), and tipranavir (TPV) in cell culture. Genotypic analysis determined the time to the appearance of protease inhibitor (PI)-associated mutations compared to HIV-1. Phenotypic drug susceptibility assays were used to determine the levels of drug resistance. Within 10 to 15 weeks of serial passage, three major mutations--I54M, I82F, and L90M--arose in HIV-2 viral cultures exposed to APV, NFV, and IDV, whereas I82L was selected with TPV. After 25 weeks, other cultures had developed I50V and I84V mutations. In contrast, no major PI mutations were selected in HIV-1 over this period except for D30N in the context of NFV selective pressure. The baseline phenotypes of wild-type HIV-2 isolates were in the range observed for HIV-1, except for APV and NFV for which a lower degree of sensitivity was seen. The acquisition of the I54M, I84V, L90M, and L99F mutations resulted in multi-PI-resistant viruses, conferring 10-fold to more than 100-fold resistance. Of note, we observed a 62A/99F mutational motif that conferred high-level resistance to PIs, as well as novel secondary mutations, including 6F, 12A, and 21K. Thus, natural polymorphisms in HIV-2 may facilitate the selection of PI resistance. The increasing incidence of such polymorphisms in drug-naive HIV-1- and HIV-2-infected persons is of concern.
|
Antiviral activity against HIV2 isolate CBL20, CBL23, MVP15132 with 150V mutation in CBMCs
|
Human immunodeficiency virus 2
|
132.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Natural polymorphisms in the human immunodeficiency virus type 2 protease can accelerate time to development of resistance to protease inhibitors.
Year : 2007
Volume : 51
Issue : 2
First Page : 604
Last Page : 610
Authors : Ntemgwa M, Brenner BG, Oliveira M, Moisi D, Wainberg MA.
Abstract : Human immunodeficiency virus type 2 (HIV-2) contains numerous natural polymorphisms in its protease (PR) gene that are implicated in drug resistance in the case of HIV-1. This study evaluated emergent PR resistance in HIV-2. Three HIV-2 isolates were selected for resistance to amprenavir (APV), nelfinavir (NFV), indinavir (IDV), and tipranavir (TPV) in cell culture. Genotypic analysis determined the time to the appearance of protease inhibitor (PI)-associated mutations compared to HIV-1. Phenotypic drug susceptibility assays were used to determine the levels of drug resistance. Within 10 to 15 weeks of serial passage, three major mutations--I54M, I82F, and L90M--arose in HIV-2 viral cultures exposed to APV, NFV, and IDV, whereas I82L was selected with TPV. After 25 weeks, other cultures had developed I50V and I84V mutations. In contrast, no major PI mutations were selected in HIV-1 over this period except for D30N in the context of NFV selective pressure. The baseline phenotypes of wild-type HIV-2 isolates were in the range observed for HIV-1, except for APV and NFV for which a lower degree of sensitivity was seen. The acquisition of the I54M, I84V, L90M, and L99F mutations resulted in multi-PI-resistant viruses, conferring 10-fold to more than 100-fold resistance. Of note, we observed a 62A/99F mutational motif that conferred high-level resistance to PIs, as well as novel secondary mutations, including 6F, 12A, and 21K. Thus, natural polymorphisms in HIV-2 may facilitate the selection of PI resistance. The increasing incidence of such polymorphisms in drug-naive HIV-1- and HIV-2-infected persons is of concern.
|
Antiviral activity against HIV2 isolate CBL20, CBL23, MVP15132 with 154M mutation in CBMCs
|
Human immunodeficiency virus 2
|
624.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Natural polymorphisms in the human immunodeficiency virus type 2 protease can accelerate time to development of resistance to protease inhibitors.
Year : 2007
Volume : 51
Issue : 2
First Page : 604
Last Page : 610
Authors : Ntemgwa M, Brenner BG, Oliveira M, Moisi D, Wainberg MA.
Abstract : Human immunodeficiency virus type 2 (HIV-2) contains numerous natural polymorphisms in its protease (PR) gene that are implicated in drug resistance in the case of HIV-1. This study evaluated emergent PR resistance in HIV-2. Three HIV-2 isolates were selected for resistance to amprenavir (APV), nelfinavir (NFV), indinavir (IDV), and tipranavir (TPV) in cell culture. Genotypic analysis determined the time to the appearance of protease inhibitor (PI)-associated mutations compared to HIV-1. Phenotypic drug susceptibility assays were used to determine the levels of drug resistance. Within 10 to 15 weeks of serial passage, three major mutations--I54M, I82F, and L90M--arose in HIV-2 viral cultures exposed to APV, NFV, and IDV, whereas I82L was selected with TPV. After 25 weeks, other cultures had developed I50V and I84V mutations. In contrast, no major PI mutations were selected in HIV-1 over this period except for D30N in the context of NFV selective pressure. The baseline phenotypes of wild-type HIV-2 isolates were in the range observed for HIV-1, except for APV and NFV for which a lower degree of sensitivity was seen. The acquisition of the I54M, I84V, L90M, and L99F mutations resulted in multi-PI-resistant viruses, conferring 10-fold to more than 100-fold resistance. Of note, we observed a 62A/99F mutational motif that conferred high-level resistance to PIs, as well as novel secondary mutations, including 6F, 12A, and 21K. Thus, natural polymorphisms in HIV-2 may facilitate the selection of PI resistance. The increasing incidence of such polymorphisms in drug-naive HIV-1- and HIV-2-infected persons is of concern.
|
Antiviral activity against wild type HIV1 in CBMCs
|
Human immunodeficiency virus 1
|
14.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Natural polymorphisms in the human immunodeficiency virus type 2 protease can accelerate time to development of resistance to protease inhibitors.
Year : 2007
Volume : 51
Issue : 2
First Page : 604
Last Page : 610
Authors : Ntemgwa M, Brenner BG, Oliveira M, Moisi D, Wainberg MA.
Abstract : Human immunodeficiency virus type 2 (HIV-2) contains numerous natural polymorphisms in its protease (PR) gene that are implicated in drug resistance in the case of HIV-1. This study evaluated emergent PR resistance in HIV-2. Three HIV-2 isolates were selected for resistance to amprenavir (APV), nelfinavir (NFV), indinavir (IDV), and tipranavir (TPV) in cell culture. Genotypic analysis determined the time to the appearance of protease inhibitor (PI)-associated mutations compared to HIV-1. Phenotypic drug susceptibility assays were used to determine the levels of drug resistance. Within 10 to 15 weeks of serial passage, three major mutations--I54M, I82F, and L90M--arose in HIV-2 viral cultures exposed to APV, NFV, and IDV, whereas I82L was selected with TPV. After 25 weeks, other cultures had developed I50V and I84V mutations. In contrast, no major PI mutations were selected in HIV-1 over this period except for D30N in the context of NFV selective pressure. The baseline phenotypes of wild-type HIV-2 isolates were in the range observed for HIV-1, except for APV and NFV for which a lower degree of sensitivity was seen. The acquisition of the I54M, I84V, L90M, and L99F mutations resulted in multi-PI-resistant viruses, conferring 10-fold to more than 100-fold resistance. Of note, we observed a 62A/99F mutational motif that conferred high-level resistance to PIs, as well as novel secondary mutations, including 6F, 12A, and 21K. Thus, natural polymorphisms in HIV-2 may facilitate the selection of PI resistance. The increasing incidence of such polymorphisms in drug-naive HIV-1- and HIV-2-infected persons is of concern.
|
Antiviral activity against HIV1 isolate 5512 with V321 and M46L mutation in CBMCs
|
Human immunodeficiency virus 1
|
31.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Natural polymorphisms in the human immunodeficiency virus type 2 protease can accelerate time to development of resistance to protease inhibitors.
Year : 2007
Volume : 51
Issue : 2
First Page : 604
Last Page : 610
Authors : Ntemgwa M, Brenner BG, Oliveira M, Moisi D, Wainberg MA.
Abstract : Human immunodeficiency virus type 2 (HIV-2) contains numerous natural polymorphisms in its protease (PR) gene that are implicated in drug resistance in the case of HIV-1. This study evaluated emergent PR resistance in HIV-2. Three HIV-2 isolates were selected for resistance to amprenavir (APV), nelfinavir (NFV), indinavir (IDV), and tipranavir (TPV) in cell culture. Genotypic analysis determined the time to the appearance of protease inhibitor (PI)-associated mutations compared to HIV-1. Phenotypic drug susceptibility assays were used to determine the levels of drug resistance. Within 10 to 15 weeks of serial passage, three major mutations--I54M, I82F, and L90M--arose in HIV-2 viral cultures exposed to APV, NFV, and IDV, whereas I82L was selected with TPV. After 25 weeks, other cultures had developed I50V and I84V mutations. In contrast, no major PI mutations were selected in HIV-1 over this period except for D30N in the context of NFV selective pressure. The baseline phenotypes of wild-type HIV-2 isolates were in the range observed for HIV-1, except for APV and NFV for which a lower degree of sensitivity was seen. The acquisition of the I54M, I84V, L90M, and L99F mutations resulted in multi-PI-resistant viruses, conferring 10-fold to more than 100-fold resistance. Of note, we observed a 62A/99F mutational motif that conferred high-level resistance to PIs, as well as novel secondary mutations, including 6F, 12A, and 21K. Thus, natural polymorphisms in HIV-2 may facilitate the selection of PI resistance. The increasing incidence of such polymorphisms in drug-naive HIV-1- and HIV-2-infected persons is of concern.
|
Antiviral activity against HIV1 isolate 5512 with D30N, M461 and V771 mutation in CBMCs
|
Human immunodeficiency virus 1
|
677.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Natural polymorphisms in the human immunodeficiency virus type 2 protease can accelerate time to development of resistance to protease inhibitors.
Year : 2007
Volume : 51
Issue : 2
First Page : 604
Last Page : 610
Authors : Ntemgwa M, Brenner BG, Oliveira M, Moisi D, Wainberg MA.
Abstract : Human immunodeficiency virus type 2 (HIV-2) contains numerous natural polymorphisms in its protease (PR) gene that are implicated in drug resistance in the case of HIV-1. This study evaluated emergent PR resistance in HIV-2. Three HIV-2 isolates were selected for resistance to amprenavir (APV), nelfinavir (NFV), indinavir (IDV), and tipranavir (TPV) in cell culture. Genotypic analysis determined the time to the appearance of protease inhibitor (PI)-associated mutations compared to HIV-1. Phenotypic drug susceptibility assays were used to determine the levels of drug resistance. Within 10 to 15 weeks of serial passage, three major mutations--I54M, I82F, and L90M--arose in HIV-2 viral cultures exposed to APV, NFV, and IDV, whereas I82L was selected with TPV. After 25 weeks, other cultures had developed I50V and I84V mutations. In contrast, no major PI mutations were selected in HIV-1 over this period except for D30N in the context of NFV selective pressure. The baseline phenotypes of wild-type HIV-2 isolates were in the range observed for HIV-1, except for APV and NFV for which a lower degree of sensitivity was seen. The acquisition of the I54M, I84V, L90M, and L99F mutations resulted in multi-PI-resistant viruses, conferring 10-fold to more than 100-fold resistance. Of note, we observed a 62A/99F mutational motif that conferred high-level resistance to PIs, as well as novel secondary mutations, including 6F, 12A, and 21K. Thus, natural polymorphisms in HIV-2 may facilitate the selection of PI resistance. The increasing incidence of such polymorphisms in drug-naive HIV-1- and HIV-2-infected persons is of concern.
|
Antiviral activity against HIV1 isolate 5512 with M36I/M and V82T mutation in CBMCs
|
Human immunodeficiency virus 1
|
10.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Natural polymorphisms in the human immunodeficiency virus type 2 protease can accelerate time to development of resistance to protease inhibitors.
Year : 2007
Volume : 51
Issue : 2
First Page : 604
Last Page : 610
Authors : Ntemgwa M, Brenner BG, Oliveira M, Moisi D, Wainberg MA.
Abstract : Human immunodeficiency virus type 2 (HIV-2) contains numerous natural polymorphisms in its protease (PR) gene that are implicated in drug resistance in the case of HIV-1. This study evaluated emergent PR resistance in HIV-2. Three HIV-2 isolates were selected for resistance to amprenavir (APV), nelfinavir (NFV), indinavir (IDV), and tipranavir (TPV) in cell culture. Genotypic analysis determined the time to the appearance of protease inhibitor (PI)-associated mutations compared to HIV-1. Phenotypic drug susceptibility assays were used to determine the levels of drug resistance. Within 10 to 15 weeks of serial passage, three major mutations--I54M, I82F, and L90M--arose in HIV-2 viral cultures exposed to APV, NFV, and IDV, whereas I82L was selected with TPV. After 25 weeks, other cultures had developed I50V and I84V mutations. In contrast, no major PI mutations were selected in HIV-1 over this period except for D30N in the context of NFV selective pressure. The baseline phenotypes of wild-type HIV-2 isolates were in the range observed for HIV-1, except for APV and NFV for which a lower degree of sensitivity was seen. The acquisition of the I54M, I84V, L90M, and L99F mutations resulted in multi-PI-resistant viruses, conferring 10-fold to more than 100-fold resistance. Of note, we observed a 62A/99F mutational motif that conferred high-level resistance to PIs, as well as novel secondary mutations, including 6F, 12A, and 21K. Thus, natural polymorphisms in HIV-2 may facilitate the selection of PI resistance. The increasing incidence of such polymorphisms in drug-naive HIV-1- and HIV-2-infected persons is of concern.
|
Inhibition of HIV1 protease
|
Human immunodeficiency virus 1
|
0.28
nM
|
|
Journal : J. Med. Chem.
Title : A combined QM/MM approach to protein--ligand interactions: polarization effects of the HIV-1 protease on selected high affinity inhibitors.
Year : 2004
Volume : 47
Issue : 27
First Page : 6673
Last Page : 6680
Authors : Hensen C, Hermann JC, Nam K, Ma S, Gao J, Höltje HD.
Abstract : HIV-1 protease inhibitors are one of the two widely used therapeutic agents for the treatment of HIV-infected patients. The investigation of HIV-1 protease-inhibitor interactions can provide further insight for developing new compounds that are still required due to the growing problem of drug resistance. To this end, a combined QM/MM approach was used to determine electrostatic and polarization interactions on three high affinity inhibitors, nelfinavir, mozenavir, and tipranavir. The present computational results show that explicit treatment of the polarization effect is particularly important since it can contribute as much as one-third of the total electrostatic interaction energy. Further, an amino acid decomposition analysis was applied to determine contributions of individual residues to the enzyme--inhibitor interactions. It was found that the 4-hydroxy-dihydropyrone substructure of tipranavir is especially suited for extended charge delocalization by interacting with the catalytic aspartates and isoleucines of the HIV-1 protease. The calculated electron density difference maps reaffirm and provide a means of visualizing these results.
|
Inhibition of HIV protease at 1 nM
|
Human immunodeficiency virus
|
29.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and antiviral property of allophenylnorstatine-based HIV protease inhibitors incorporating D-cysteine derivatives as P2/P3 moieties.
Year : 2007
Volume : 17
Issue : 15
First Page : 4213
Last Page : 4217
Authors : Ami E, Nakahara K, Sato A, Nguyen JT, Hidaka K, Hamada Y, Nakatani S, Kimura T, Hayashi Y, Kiso Y.
Abstract : We designed several HIV protease inhibitors with various d-cysteine derivatives as P(2)/P(3) moieties based on the structure of clinical drug candidate, KNI-764. Herein, we report their synthesis, HIV protease inhibitory activity, HIV IIIB cell inhibitory activity, cellular toxicity, and inhibitory activity against drug-resistant HIV strains. KNI-1931 showed distinct selectivity against HIV proteases and high potency against drug-resistant strains, surpassing those of Ritonavir and Nelfinavir.
|
Antiviral activity against HIV1 3B in MT4 cells by MTT assay
|
Human immunodeficiency virus 1
|
16.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and antiviral property of allophenylnorstatine-based HIV protease inhibitors incorporating D-cysteine derivatives as P2/P3 moieties.
Year : 2007
Volume : 17
Issue : 15
First Page : 4213
Last Page : 4217
Authors : Ami E, Nakahara K, Sato A, Nguyen JT, Hidaka K, Hamada Y, Nakatani S, Kimura T, Hayashi Y, Kiso Y.
Abstract : We designed several HIV protease inhibitors with various d-cysteine derivatives as P(2)/P(3) moieties based on the structure of clinical drug candidate, KNI-764. Herein, we report their synthesis, HIV protease inhibitory activity, HIV IIIB cell inhibitory activity, cellular toxicity, and inhibitory activity against drug-resistant HIV strains. KNI-1931 showed distinct selectivity against HIV proteases and high potency against drug-resistant strains, surpassing those of Ritonavir and Nelfinavir.
|
Antiviral activity against HIV1 NL432
|
Human immunodeficiency virus 1
|
25.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and antiviral property of allophenylnorstatine-based HIV protease inhibitors incorporating D-cysteine derivatives as P2/P3 moieties.
Year : 2007
Volume : 17
Issue : 15
First Page : 4213
Last Page : 4217
Authors : Ami E, Nakahara K, Sato A, Nguyen JT, Hidaka K, Hamada Y, Nakatani S, Kimura T, Hayashi Y, Kiso Y.
Abstract : We designed several HIV protease inhibitors with various d-cysteine derivatives as P(2)/P(3) moieties based on the structure of clinical drug candidate, KNI-764. Herein, we report their synthesis, HIV protease inhibitory activity, HIV IIIB cell inhibitory activity, cellular toxicity, and inhibitory activity against drug-resistant HIV strains. KNI-1931 showed distinct selectivity against HIV proteases and high potency against drug-resistant strains, surpassing those of Ritonavir and Nelfinavir.
|
Antiviral activity against ritonavir-resistant HIV1 NL432
|
Human immunodeficiency virus 1
|
28.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and antiviral property of allophenylnorstatine-based HIV protease inhibitors incorporating D-cysteine derivatives as P2/P3 moieties.
Year : 2007
Volume : 17
Issue : 15
First Page : 4213
Last Page : 4217
Authors : Ami E, Nakahara K, Sato A, Nguyen JT, Hidaka K, Hamada Y, Nakatani S, Kimura T, Hayashi Y, Kiso Y.
Abstract : We designed several HIV protease inhibitors with various d-cysteine derivatives as P(2)/P(3) moieties based on the structure of clinical drug candidate, KNI-764. Herein, we report their synthesis, HIV protease inhibitory activity, HIV IIIB cell inhibitory activity, cellular toxicity, and inhibitory activity against drug-resistant HIV strains. KNI-1931 showed distinct selectivity against HIV proteases and high potency against drug-resistant strains, surpassing those of Ritonavir and Nelfinavir.
|
Antiviral activity against nelfinavir-resistant HIV1 NL432
|
Human immunodeficiency virus 1
|
308.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and antiviral property of allophenylnorstatine-based HIV protease inhibitors incorporating D-cysteine derivatives as P2/P3 moieties.
Year : 2007
Volume : 17
Issue : 15
First Page : 4213
Last Page : 4217
Authors : Ami E, Nakahara K, Sato A, Nguyen JT, Hidaka K, Hamada Y, Nakatani S, Kimura T, Hayashi Y, Kiso Y.
Abstract : We designed several HIV protease inhibitors with various d-cysteine derivatives as P(2)/P(3) moieties based on the structure of clinical drug candidate, KNI-764. Herein, we report their synthesis, HIV protease inhibitory activity, HIV IIIB cell inhibitory activity, cellular toxicity, and inhibitory activity against drug-resistant HIV strains. KNI-1931 showed distinct selectivity against HIV proteases and high potency against drug-resistant strains, surpassing those of Ritonavir and Nelfinavir.
|
Antiviral activity against ritonavir and nelfinavir-resistant HIV1 NL432
|
Human immunodeficiency virus 1
|
67.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and antiviral property of allophenylnorstatine-based HIV protease inhibitors incorporating D-cysteine derivatives as P2/P3 moieties.
Year : 2007
Volume : 17
Issue : 15
First Page : 4213
Last Page : 4217
Authors : Ami E, Nakahara K, Sato A, Nguyen JT, Hidaka K, Hamada Y, Nakatani S, Kimura T, Hayashi Y, Kiso Y.
Abstract : We designed several HIV protease inhibitors with various d-cysteine derivatives as P(2)/P(3) moieties based on the structure of clinical drug candidate, KNI-764. Herein, we report their synthesis, HIV protease inhibitory activity, HIV IIIB cell inhibitory activity, cellular toxicity, and inhibitory activity against drug-resistant HIV strains. KNI-1931 showed distinct selectivity against HIV proteases and high potency against drug-resistant strains, surpassing those of Ritonavir and Nelfinavir.
|
Inhibition of HIV1 protease
|
Human immunodeficiency virus 1
|
0.931
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Structure-activity relationships of novel HIV-1 protease inhibitors containing the 3-amino-2-chlorobenzoyl-allophenylnorstatine structure.
Year : 2008
Volume : 16
Issue : 3
First Page : 1299
Last Page : 1308
Authors : Mimoto T, Nojima S, Terashima K, Takaku H, Shintani M, Hayashi H.
Abstract : A series of peptidomimetic human immunodeficiency virus (HIV) protease inhibitors containing substituted allophenylnorstatine (Apns: (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid) were designed and synthesized. From the structure-activity relationship of this series of compounds, SM-309515 was found to have potent antiviral activity against wild-type and resistant HIV-1s and to possess a desirable pharmacokinetic profile in dogs.
|
Antiviral activity against HIV1 3B
|
Human immunodeficiency virus 1
|
19.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Structure-activity relationships of novel HIV-1 protease inhibitors containing the 3-amino-2-chlorobenzoyl-allophenylnorstatine structure.
Year : 2008
Volume : 16
Issue : 3
First Page : 1299
Last Page : 1308
Authors : Mimoto T, Nojima S, Terashima K, Takaku H, Shintani M, Hayashi H.
Abstract : A series of peptidomimetic human immunodeficiency virus (HIV) protease inhibitors containing substituted allophenylnorstatine (Apns: (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid) were designed and synthesized. From the structure-activity relationship of this series of compounds, SM-309515 was found to have potent antiviral activity against wild-type and resistant HIV-1s and to possess a desirable pharmacokinetic profile in dogs.
|
Antiviral activity against HIV1 3B in presence of 50% human serum
|
Human immunodeficiency virus 1
|
293.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Structure-activity relationships of novel HIV-1 protease inhibitors containing the 3-amino-2-chlorobenzoyl-allophenylnorstatine structure.
Year : 2008
Volume : 16
Issue : 3
First Page : 1299
Last Page : 1308
Authors : Mimoto T, Nojima S, Terashima K, Takaku H, Shintani M, Hayashi H.
Abstract : A series of peptidomimetic human immunodeficiency virus (HIV) protease inhibitors containing substituted allophenylnorstatine (Apns: (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid) were designed and synthesized. From the structure-activity relationship of this series of compounds, SM-309515 was found to have potent antiviral activity against wild-type and resistant HIV-1s and to possess a desirable pharmacokinetic profile in dogs.
|
Antiviral activity against wild type HIV1
|
Human immunodeficiency virus 1
|
5.4
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Structure-activity relationships of novel HIV-1 protease inhibitors containing the 3-amino-2-chlorobenzoyl-allophenylnorstatine structure.
Year : 2008
Volume : 16
Issue : 3
First Page : 1299
Last Page : 1308
Authors : Mimoto T, Nojima S, Terashima K, Takaku H, Shintani M, Hayashi H.
Abstract : A series of peptidomimetic human immunodeficiency virus (HIV) protease inhibitors containing substituted allophenylnorstatine (Apns: (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid) were designed and synthesized. From the structure-activity relationship of this series of compounds, SM-309515 was found to have potent antiviral activity against wild-type and resistant HIV-1s and to possess a desirable pharmacokinetic profile in dogs.
|
Antiviral activity against HIV1 mutant strain 1
|
Human immunodeficiency virus 1
|
452.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Structure-activity relationships of novel HIV-1 protease inhibitors containing the 3-amino-2-chlorobenzoyl-allophenylnorstatine structure.
Year : 2008
Volume : 16
Issue : 3
First Page : 1299
Last Page : 1308
Authors : Mimoto T, Nojima S, Terashima K, Takaku H, Shintani M, Hayashi H.
Abstract : A series of peptidomimetic human immunodeficiency virus (HIV) protease inhibitors containing substituted allophenylnorstatine (Apns: (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid) were designed and synthesized. From the structure-activity relationship of this series of compounds, SM-309515 was found to have potent antiviral activity against wild-type and resistant HIV-1s and to possess a desirable pharmacokinetic profile in dogs.
|
Antiviral activity against HIV1 mutant strain 2
|
Human immunodeficiency virus 1
|
346.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Structure-activity relationships of novel HIV-1 protease inhibitors containing the 3-amino-2-chlorobenzoyl-allophenylnorstatine structure.
Year : 2008
Volume : 16
Issue : 3
First Page : 1299
Last Page : 1308
Authors : Mimoto T, Nojima S, Terashima K, Takaku H, Shintani M, Hayashi H.
Abstract : A series of peptidomimetic human immunodeficiency virus (HIV) protease inhibitors containing substituted allophenylnorstatine (Apns: (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid) were designed and synthesized. From the structure-activity relationship of this series of compounds, SM-309515 was found to have potent antiviral activity against wild-type and resistant HIV-1s and to possess a desirable pharmacokinetic profile in dogs.
|
Antiviral activity against HIV1 mutant strain 3
|
Human immunodeficiency virus 1
|
413.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Structure-activity relationships of novel HIV-1 protease inhibitors containing the 3-amino-2-chlorobenzoyl-allophenylnorstatine structure.
Year : 2008
Volume : 16
Issue : 3
First Page : 1299
Last Page : 1308
Authors : Mimoto T, Nojima S, Terashima K, Takaku H, Shintani M, Hayashi H.
Abstract : A series of peptidomimetic human immunodeficiency virus (HIV) protease inhibitors containing substituted allophenylnorstatine (Apns: (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid) were designed and synthesized. From the structure-activity relationship of this series of compounds, SM-309515 was found to have potent antiviral activity against wild-type and resistant HIV-1s and to possess a desirable pharmacokinetic profile in dogs.
|
Antiviral activity against HIV1 mutant strain 5
|
Human immunodeficiency virus 1
|
776.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Structure-activity relationships of novel HIV-1 protease inhibitors containing the 3-amino-2-chlorobenzoyl-allophenylnorstatine structure.
Year : 2008
Volume : 16
Issue : 3
First Page : 1299
Last Page : 1308
Authors : Mimoto T, Nojima S, Terashima K, Takaku H, Shintani M, Hayashi H.
Abstract : A series of peptidomimetic human immunodeficiency virus (HIV) protease inhibitors containing substituted allophenylnorstatine (Apns: (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid) were designed and synthesized. From the structure-activity relationship of this series of compounds, SM-309515 was found to have potent antiviral activity against wild-type and resistant HIV-1s and to possess a desirable pharmacokinetic profile in dogs.
|
Antiviral activity against HIV1 mutant strain 7
|
Human immunodeficiency virus 1
|
515.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Structure-activity relationships of novel HIV-1 protease inhibitors containing the 3-amino-2-chlorobenzoyl-allophenylnorstatine structure.
Year : 2008
Volume : 16
Issue : 3
First Page : 1299
Last Page : 1308
Authors : Mimoto T, Nojima S, Terashima K, Takaku H, Shintani M, Hayashi H.
Abstract : A series of peptidomimetic human immunodeficiency virus (HIV) protease inhibitors containing substituted allophenylnorstatine (Apns: (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid) were designed and synthesized. From the structure-activity relationship of this series of compounds, SM-309515 was found to have potent antiviral activity against wild-type and resistant HIV-1s and to possess a desirable pharmacokinetic profile in dogs.
|
Antiviral activity against HIV1 LAI in MT2 cells assessed as inhibition of p24 Gag protein expression by MTT assay
|
Human immunodeficiency virus 1
|
32.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : A novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI), GRL-98065, is potent against multiple-PI-resistant human immunodeficiency virus in vitro.
Year : 2007
Volume : 51
Issue : 6
First Page : 2143
Last Page : 2155
Authors : Amano M, Koh Y, Das D, Li J, Leschenko S, Wang YF, Boross PI, Weber IT, Ghosh AK, Mitsuya H.
Abstract : We designed, synthesized, and identified GRL-98065, a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) containing the structure-based designed privileged cyclic ether-derived nonpeptide P2 ligand, 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane (bis-THF), and a sulfonamide isostere, which is highly potent against laboratory HIV-1 strains and primary clinical isolates (50% effective concentration [EC(50)], 0.0002 to 0.0005 microM) with minimal cytotoxicity (50% cytotoxicity, 35.7 microM in CD4(+) MT-2 cells). GRL-98065 blocked the infectivity and replication of each of the HIV-1(NL4-3) variants exposed to and selected by up to a 5 microM concentration of saquinavir, indinavir, nelfinavir, or ritonavir and a 1 microM concentration of lopinavir or atazanavir (EC(50), 0.0015 to 0.0075 microM), although it was less active against HIV-1(NL4-3) selected by amprenavir (EC(50), 0.032 microM). GRL-98065 was also potent against multiple-PI-resistant clinical HIV-1 variants isolated from patients who had no response to existing antiviral regimens after having received a variety of antiviral agents, HIV-1 isolates of various subtypes, and HIV-2 isolates examined. Structural analyses revealed that the close contact of GRL-98065 with the main chain of the protease active-site amino acids (Asp29 and Asp30) is important for its potency and wide-spectrum activity against multiple-PI-resistant HIV-1 variants. The present data demonstrate that the privileged nonpeptide P2 ligand, bis-THF, is critical for the binding of GRL-98065 to the HIV protease substrate binding site and that this scaffold can confer highly potent antiviral activity against a wide spectrum of HIV isolates.
|
Antiviral activity against HIV2 EHO in MT2 cells assessed as inhibition of p24 Gag protein expression by MTT assay
|
Human immunodeficiency virus 2
|
30.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : A novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI), GRL-98065, is potent against multiple-PI-resistant human immunodeficiency virus in vitro.
Year : 2007
Volume : 51
Issue : 6
First Page : 2143
Last Page : 2155
Authors : Amano M, Koh Y, Das D, Li J, Leschenko S, Wang YF, Boross PI, Weber IT, Ghosh AK, Mitsuya H.
Abstract : We designed, synthesized, and identified GRL-98065, a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) containing the structure-based designed privileged cyclic ether-derived nonpeptide P2 ligand, 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane (bis-THF), and a sulfonamide isostere, which is highly potent against laboratory HIV-1 strains and primary clinical isolates (50% effective concentration [EC(50)], 0.0002 to 0.0005 microM) with minimal cytotoxicity (50% cytotoxicity, 35.7 microM in CD4(+) MT-2 cells). GRL-98065 blocked the infectivity and replication of each of the HIV-1(NL4-3) variants exposed to and selected by up to a 5 microM concentration of saquinavir, indinavir, nelfinavir, or ritonavir and a 1 microM concentration of lopinavir or atazanavir (EC(50), 0.0015 to 0.0075 microM), although it was less active against HIV-1(NL4-3) selected by amprenavir (EC(50), 0.032 microM). GRL-98065 was also potent against multiple-PI-resistant clinical HIV-1 variants isolated from patients who had no response to existing antiviral regimens after having received a variety of antiviral agents, HIV-1 isolates of various subtypes, and HIV-2 isolates examined. Structural analyses revealed that the close contact of GRL-98065 with the main chain of the protease active-site amino acids (Asp29 and Asp30) is important for its potency and wide-spectrum activity against multiple-PI-resistant HIV-1 variants. The present data demonstrate that the privileged nonpeptide P2 ligand, bis-THF, is critical for the binding of GRL-98065 to the HIV protease substrate binding site and that this scaffold can confer highly potent antiviral activity against a wide spectrum of HIV isolates.
|
Antiviral activity against HIV2 ROD in MT2 cells assessed as inhibition of p24 Gag protein expression by MTT assay
|
Human immunodeficiency virus 2
|
240.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : A novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI), GRL-98065, is potent against multiple-PI-resistant human immunodeficiency virus in vitro.
Year : 2007
Volume : 51
Issue : 6
First Page : 2143
Last Page : 2155
Authors : Amano M, Koh Y, Das D, Li J, Leschenko S, Wang YF, Boross PI, Weber IT, Ghosh AK, Mitsuya H.
Abstract : We designed, synthesized, and identified GRL-98065, a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) containing the structure-based designed privileged cyclic ether-derived nonpeptide P2 ligand, 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane (bis-THF), and a sulfonamide isostere, which is highly potent against laboratory HIV-1 strains and primary clinical isolates (50% effective concentration [EC(50)], 0.0002 to 0.0005 microM) with minimal cytotoxicity (50% cytotoxicity, 35.7 microM in CD4(+) MT-2 cells). GRL-98065 blocked the infectivity and replication of each of the HIV-1(NL4-3) variants exposed to and selected by up to a 5 microM concentration of saquinavir, indinavir, nelfinavir, or ritonavir and a 1 microM concentration of lopinavir or atazanavir (EC(50), 0.0015 to 0.0075 microM), although it was less active against HIV-1(NL4-3) selected by amprenavir (EC(50), 0.032 microM). GRL-98065 was also potent against multiple-PI-resistant clinical HIV-1 variants isolated from patients who had no response to existing antiviral regimens after having received a variety of antiviral agents, HIV-1 isolates of various subtypes, and HIV-2 isolates examined. Structural analyses revealed that the close contact of GRL-98065 with the main chain of the protease active-site amino acids (Asp29 and Asp30) is important for its potency and wide-spectrum activity against multiple-PI-resistant HIV-1 variants. The present data demonstrate that the privileged nonpeptide P2 ligand, bis-THF, is critical for the binding of GRL-98065 to the HIV protease substrate binding site and that this scaffold can confer highly potent antiviral activity against a wide spectrum of HIV isolates.
|
Antiviral activity against HIV1 NL4-3 in MT4 cells by MTT assay
|
Human immunodeficiency virus 1
|
33.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : A novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI), GRL-98065, is potent against multiple-PI-resistant human immunodeficiency virus in vitro.
Year : 2007
Volume : 51
Issue : 6
First Page : 2143
Last Page : 2155
Authors : Amano M, Koh Y, Das D, Li J, Leschenko S, Wang YF, Boross PI, Weber IT, Ghosh AK, Mitsuya H.
Abstract : We designed, synthesized, and identified GRL-98065, a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) containing the structure-based designed privileged cyclic ether-derived nonpeptide P2 ligand, 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane (bis-THF), and a sulfonamide isostere, which is highly potent against laboratory HIV-1 strains and primary clinical isolates (50% effective concentration [EC(50)], 0.0002 to 0.0005 microM) with minimal cytotoxicity (50% cytotoxicity, 35.7 microM in CD4(+) MT-2 cells). GRL-98065 blocked the infectivity and replication of each of the HIV-1(NL4-3) variants exposed to and selected by up to a 5 microM concentration of saquinavir, indinavir, nelfinavir, or ritonavir and a 1 microM concentration of lopinavir or atazanavir (EC(50), 0.0015 to 0.0075 microM), although it was less active against HIV-1(NL4-3) selected by amprenavir (EC(50), 0.032 microM). GRL-98065 was also potent against multiple-PI-resistant clinical HIV-1 variants isolated from patients who had no response to existing antiviral regimens after having received a variety of antiviral agents, HIV-1 isolates of various subtypes, and HIV-2 isolates examined. Structural analyses revealed that the close contact of GRL-98065 with the main chain of the protease active-site amino acids (Asp29 and Asp30) is important for its potency and wide-spectrum activity against multiple-PI-resistant HIV-1 variants. The present data demonstrate that the privileged nonpeptide P2 ligand, bis-THF, is critical for the binding of GRL-98065 to the HIV protease substrate binding site and that this scaffold can confer highly potent antiviral activity against a wide spectrum of HIV isolates.
|
Antiviral activity against saquinavir-resistant HIV1 in MT4 cells assessed as inhibition of p24 Gag protein expression by MTT assay
|
Human immunodeficiency virus 1
|
480.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : A novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI), GRL-98065, is potent against multiple-PI-resistant human immunodeficiency virus in vitro.
Year : 2007
Volume : 51
Issue : 6
First Page : 2143
Last Page : 2155
Authors : Amano M, Koh Y, Das D, Li J, Leschenko S, Wang YF, Boross PI, Weber IT, Ghosh AK, Mitsuya H.
Abstract : We designed, synthesized, and identified GRL-98065, a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) containing the structure-based designed privileged cyclic ether-derived nonpeptide P2 ligand, 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane (bis-THF), and a sulfonamide isostere, which is highly potent against laboratory HIV-1 strains and primary clinical isolates (50% effective concentration [EC(50)], 0.0002 to 0.0005 microM) with minimal cytotoxicity (50% cytotoxicity, 35.7 microM in CD4(+) MT-2 cells). GRL-98065 blocked the infectivity and replication of each of the HIV-1(NL4-3) variants exposed to and selected by up to a 5 microM concentration of saquinavir, indinavir, nelfinavir, or ritonavir and a 1 microM concentration of lopinavir or atazanavir (EC(50), 0.0015 to 0.0075 microM), although it was less active against HIV-1(NL4-3) selected by amprenavir (EC(50), 0.032 microM). GRL-98065 was also potent against multiple-PI-resistant clinical HIV-1 variants isolated from patients who had no response to existing antiviral regimens after having received a variety of antiviral agents, HIV-1 isolates of various subtypes, and HIV-2 isolates examined. Structural analyses revealed that the close contact of GRL-98065 with the main chain of the protease active-site amino acids (Asp29 and Asp30) is important for its potency and wide-spectrum activity against multiple-PI-resistant HIV-1 variants. The present data demonstrate that the privileged nonpeptide P2 ligand, bis-THF, is critical for the binding of GRL-98065 to the HIV protease substrate binding site and that this scaffold can confer highly potent antiviral activity against a wide spectrum of HIV isolates.
|
Antiviral activity against ritonavir-resistant HIV1 in MT4 cells assessed as inhibition of p24 Gag protein expression by MTT assay
|
Human immunodeficiency virus 1
|
210.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : A novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI), GRL-98065, is potent against multiple-PI-resistant human immunodeficiency virus in vitro.
Year : 2007
Volume : 51
Issue : 6
First Page : 2143
Last Page : 2155
Authors : Amano M, Koh Y, Das D, Li J, Leschenko S, Wang YF, Boross PI, Weber IT, Ghosh AK, Mitsuya H.
Abstract : We designed, synthesized, and identified GRL-98065, a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) containing the structure-based designed privileged cyclic ether-derived nonpeptide P2 ligand, 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane (bis-THF), and a sulfonamide isostere, which is highly potent against laboratory HIV-1 strains and primary clinical isolates (50% effective concentration [EC(50)], 0.0002 to 0.0005 microM) with minimal cytotoxicity (50% cytotoxicity, 35.7 microM in CD4(+) MT-2 cells). GRL-98065 blocked the infectivity and replication of each of the HIV-1(NL4-3) variants exposed to and selected by up to a 5 microM concentration of saquinavir, indinavir, nelfinavir, or ritonavir and a 1 microM concentration of lopinavir or atazanavir (EC(50), 0.0015 to 0.0075 microM), although it was less active against HIV-1(NL4-3) selected by amprenavir (EC(50), 0.032 microM). GRL-98065 was also potent against multiple-PI-resistant clinical HIV-1 variants isolated from patients who had no response to existing antiviral regimens after having received a variety of antiviral agents, HIV-1 isolates of various subtypes, and HIV-2 isolates examined. Structural analyses revealed that the close contact of GRL-98065 with the main chain of the protease active-site amino acids (Asp29 and Asp30) is important for its potency and wide-spectrum activity against multiple-PI-resistant HIV-1 variants. The present data demonstrate that the privileged nonpeptide P2 ligand, bis-THF, is critical for the binding of GRL-98065 to the HIV protease substrate binding site and that this scaffold can confer highly potent antiviral activity against a wide spectrum of HIV isolates.
|
Antiviral activity against idinavir-resistant HIV1 in MT4 cells assessed as inhibition of p24 Gag protein expression by MTT assay
|
Human immunodeficiency virus 1
|
470.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : A novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI), GRL-98065, is potent against multiple-PI-resistant human immunodeficiency virus in vitro.
Year : 2007
Volume : 51
Issue : 6
First Page : 2143
Last Page : 2155
Authors : Amano M, Koh Y, Das D, Li J, Leschenko S, Wang YF, Boross PI, Weber IT, Ghosh AK, Mitsuya H.
Abstract : We designed, synthesized, and identified GRL-98065, a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) containing the structure-based designed privileged cyclic ether-derived nonpeptide P2 ligand, 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane (bis-THF), and a sulfonamide isostere, which is highly potent against laboratory HIV-1 strains and primary clinical isolates (50% effective concentration [EC(50)], 0.0002 to 0.0005 microM) with minimal cytotoxicity (50% cytotoxicity, 35.7 microM in CD4(+) MT-2 cells). GRL-98065 blocked the infectivity and replication of each of the HIV-1(NL4-3) variants exposed to and selected by up to a 5 microM concentration of saquinavir, indinavir, nelfinavir, or ritonavir and a 1 microM concentration of lopinavir or atazanavir (EC(50), 0.0015 to 0.0075 microM), although it was less active against HIV-1(NL4-3) selected by amprenavir (EC(50), 0.032 microM). GRL-98065 was also potent against multiple-PI-resistant clinical HIV-1 variants isolated from patients who had no response to existing antiviral regimens after having received a variety of antiviral agents, HIV-1 isolates of various subtypes, and HIV-2 isolates examined. Structural analyses revealed that the close contact of GRL-98065 with the main chain of the protease active-site amino acids (Asp29 and Asp30) is important for its potency and wide-spectrum activity against multiple-PI-resistant HIV-1 variants. The present data demonstrate that the privileged nonpeptide P2 ligand, bis-THF, is critical for the binding of GRL-98065 to the HIV protease substrate binding site and that this scaffold can confer highly potent antiviral activity against a wide spectrum of HIV isolates.
|
Antiviral activity against atazanavir-resistant HIV1 in MT4 cells assessed as inhibition of p24 Gag protein expression by MTT assay
|
Human immunodeficiency virus 1
|
270.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : A novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI), GRL-98065, is potent against multiple-PI-resistant human immunodeficiency virus in vitro.
Year : 2007
Volume : 51
Issue : 6
First Page : 2143
Last Page : 2155
Authors : Amano M, Koh Y, Das D, Li J, Leschenko S, Wang YF, Boross PI, Weber IT, Ghosh AK, Mitsuya H.
Abstract : We designed, synthesized, and identified GRL-98065, a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) containing the structure-based designed privileged cyclic ether-derived nonpeptide P2 ligand, 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane (bis-THF), and a sulfonamide isostere, which is highly potent against laboratory HIV-1 strains and primary clinical isolates (50% effective concentration [EC(50)], 0.0002 to 0.0005 microM) with minimal cytotoxicity (50% cytotoxicity, 35.7 microM in CD4(+) MT-2 cells). GRL-98065 blocked the infectivity and replication of each of the HIV-1(NL4-3) variants exposed to and selected by up to a 5 microM concentration of saquinavir, indinavir, nelfinavir, or ritonavir and a 1 microM concentration of lopinavir or atazanavir (EC(50), 0.0015 to 0.0075 microM), although it was less active against HIV-1(NL4-3) selected by amprenavir (EC(50), 0.032 microM). GRL-98065 was also potent against multiple-PI-resistant clinical HIV-1 variants isolated from patients who had no response to existing antiviral regimens after having received a variety of antiviral agents, HIV-1 isolates of various subtypes, and HIV-2 isolates examined. Structural analyses revealed that the close contact of GRL-98065 with the main chain of the protease active-site amino acids (Asp29 and Asp30) is important for its potency and wide-spectrum activity against multiple-PI-resistant HIV-1 variants. The present data demonstrate that the privileged nonpeptide P2 ligand, bis-THF, is critical for the binding of GRL-98065 to the HIV protease substrate binding site and that this scaffold can confer highly potent antiviral activity against a wide spectrum of HIV isolates.
|
Antiviral activity against lopinavir-resistant HIV1 in MT4 cells assessed as inhibition of p24 Gag protein expression by MTT assay
|
Human immunodeficiency virus 1
|
490.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : A novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI), GRL-98065, is potent against multiple-PI-resistant human immunodeficiency virus in vitro.
Year : 2007
Volume : 51
Issue : 6
First Page : 2143
Last Page : 2155
Authors : Amano M, Koh Y, Das D, Li J, Leschenko S, Wang YF, Boross PI, Weber IT, Ghosh AK, Mitsuya H.
Abstract : We designed, synthesized, and identified GRL-98065, a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) containing the structure-based designed privileged cyclic ether-derived nonpeptide P2 ligand, 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane (bis-THF), and a sulfonamide isostere, which is highly potent against laboratory HIV-1 strains and primary clinical isolates (50% effective concentration [EC(50)], 0.0002 to 0.0005 microM) with minimal cytotoxicity (50% cytotoxicity, 35.7 microM in CD4(+) MT-2 cells). GRL-98065 blocked the infectivity and replication of each of the HIV-1(NL4-3) variants exposed to and selected by up to a 5 microM concentration of saquinavir, indinavir, nelfinavir, or ritonavir and a 1 microM concentration of lopinavir or atazanavir (EC(50), 0.0015 to 0.0075 microM), although it was less active against HIV-1(NL4-3) selected by amprenavir (EC(50), 0.032 microM). GRL-98065 was also potent against multiple-PI-resistant clinical HIV-1 variants isolated from patients who had no response to existing antiviral regimens after having received a variety of antiviral agents, HIV-1 isolates of various subtypes, and HIV-2 isolates examined. Structural analyses revealed that the close contact of GRL-98065 with the main chain of the protease active-site amino acids (Asp29 and Asp30) is important for its potency and wide-spectrum activity against multiple-PI-resistant HIV-1 variants. The present data demonstrate that the privileged nonpeptide P2 ligand, bis-THF, is critical for the binding of GRL-98065 to the HIV protease substrate binding site and that this scaffold can confer highly potent antiviral activity against a wide spectrum of HIV isolates.
|
Antiviral activity against amprenavir-resistant HIV1 in MT4 cells assessed as inhibition of p24 Gag protein expression by MTT assay
|
Human immunodeficiency virus 1
|
220.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : A novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI), GRL-98065, is potent against multiple-PI-resistant human immunodeficiency virus in vitro.
Year : 2007
Volume : 51
Issue : 6
First Page : 2143
Last Page : 2155
Authors : Amano M, Koh Y, Das D, Li J, Leschenko S, Wang YF, Boross PI, Weber IT, Ghosh AK, Mitsuya H.
Abstract : We designed, synthesized, and identified GRL-98065, a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) containing the structure-based designed privileged cyclic ether-derived nonpeptide P2 ligand, 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane (bis-THF), and a sulfonamide isostere, which is highly potent against laboratory HIV-1 strains and primary clinical isolates (50% effective concentration [EC(50)], 0.0002 to 0.0005 microM) with minimal cytotoxicity (50% cytotoxicity, 35.7 microM in CD4(+) MT-2 cells). GRL-98065 blocked the infectivity and replication of each of the HIV-1(NL4-3) variants exposed to and selected by up to a 5 microM concentration of saquinavir, indinavir, nelfinavir, or ritonavir and a 1 microM concentration of lopinavir or atazanavir (EC(50), 0.0015 to 0.0075 microM), although it was less active against HIV-1(NL4-3) selected by amprenavir (EC(50), 0.032 microM). GRL-98065 was also potent against multiple-PI-resistant clinical HIV-1 variants isolated from patients who had no response to existing antiviral regimens after having received a variety of antiviral agents, HIV-1 isolates of various subtypes, and HIV-2 isolates examined. Structural analyses revealed that the close contact of GRL-98065 with the main chain of the protease active-site amino acids (Asp29 and Asp30) is important for its potency and wide-spectrum activity against multiple-PI-resistant HIV-1 variants. The present data demonstrate that the privileged nonpeptide P2 ligand, bis-THF, is critical for the binding of GRL-98065 to the HIV protease substrate binding site and that this scaffold can confer highly potent antiviral activity against a wide spectrum of HIV isolates.
|
Antiviral activity against HIV1 GRL98065p20 in MT4 cells assessed as inhibition of p24 Gag protein expression by MTT assay
|
Human immunodeficiency virus 1
|
80.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : A novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI), GRL-98065, is potent against multiple-PI-resistant human immunodeficiency virus in vitro.
Year : 2007
Volume : 51
Issue : 6
First Page : 2143
Last Page : 2155
Authors : Amano M, Koh Y, Das D, Li J, Leschenko S, Wang YF, Boross PI, Weber IT, Ghosh AK, Mitsuya H.
Abstract : We designed, synthesized, and identified GRL-98065, a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) containing the structure-based designed privileged cyclic ether-derived nonpeptide P2 ligand, 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane (bis-THF), and a sulfonamide isostere, which is highly potent against laboratory HIV-1 strains and primary clinical isolates (50% effective concentration [EC(50)], 0.0002 to 0.0005 microM) with minimal cytotoxicity (50% cytotoxicity, 35.7 microM in CD4(+) MT-2 cells). GRL-98065 blocked the infectivity and replication of each of the HIV-1(NL4-3) variants exposed to and selected by up to a 5 microM concentration of saquinavir, indinavir, nelfinavir, or ritonavir and a 1 microM concentration of lopinavir or atazanavir (EC(50), 0.0015 to 0.0075 microM), although it was less active against HIV-1(NL4-3) selected by amprenavir (EC(50), 0.032 microM). GRL-98065 was also potent against multiple-PI-resistant clinical HIV-1 variants isolated from patients who had no response to existing antiviral regimens after having received a variety of antiviral agents, HIV-1 isolates of various subtypes, and HIV-2 isolates examined. Structural analyses revealed that the close contact of GRL-98065 with the main chain of the protease active-site amino acids (Asp29 and Asp30) is important for its potency and wide-spectrum activity against multiple-PI-resistant HIV-1 variants. The present data demonstrate that the privileged nonpeptide P2 ligand, bis-THF, is critical for the binding of GRL-98065 to the HIV protease substrate binding site and that this scaffold can confer highly potent antiviral activity against a wide spectrum of HIV isolates.
|
Antiviral activity against HIV1 GRL98065p30 in MT4 cells assessed as inhibition of p24 Gag protein expression by MTT assay
|
Human immunodeficiency virus 1
|
270.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : A novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI), GRL-98065, is potent against multiple-PI-resistant human immunodeficiency virus in vitro.
Year : 2007
Volume : 51
Issue : 6
First Page : 2143
Last Page : 2155
Authors : Amano M, Koh Y, Das D, Li J, Leschenko S, Wang YF, Boross PI, Weber IT, Ghosh AK, Mitsuya H.
Abstract : We designed, synthesized, and identified GRL-98065, a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) containing the structure-based designed privileged cyclic ether-derived nonpeptide P2 ligand, 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane (bis-THF), and a sulfonamide isostere, which is highly potent against laboratory HIV-1 strains and primary clinical isolates (50% effective concentration [EC(50)], 0.0002 to 0.0005 microM) with minimal cytotoxicity (50% cytotoxicity, 35.7 microM in CD4(+) MT-2 cells). GRL-98065 blocked the infectivity and replication of each of the HIV-1(NL4-3) variants exposed to and selected by up to a 5 microM concentration of saquinavir, indinavir, nelfinavir, or ritonavir and a 1 microM concentration of lopinavir or atazanavir (EC(50), 0.0015 to 0.0075 microM), although it was less active against HIV-1(NL4-3) selected by amprenavir (EC(50), 0.032 microM). GRL-98065 was also potent against multiple-PI-resistant clinical HIV-1 variants isolated from patients who had no response to existing antiviral regimens after having received a variety of antiviral agents, HIV-1 isolates of various subtypes, and HIV-2 isolates examined. Structural analyses revealed that the close contact of GRL-98065 with the main chain of the protease active-site amino acids (Asp29 and Asp30) is important for its potency and wide-spectrum activity against multiple-PI-resistant HIV-1 variants. The present data demonstrate that the privileged nonpeptide P2 ligand, bis-THF, is critical for the binding of GRL-98065 to the HIV protease substrate binding site and that this scaffold can confer highly potent antiviral activity against a wide spectrum of HIV isolates.
|
Antiviral activity against HIV1 GRL98065p40 in MT4 cells assessed as inhibition of p24 Gag protein expression by MTT assay
|
Human immunodeficiency virus 1
|
340.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : A novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI), GRL-98065, is potent against multiple-PI-resistant human immunodeficiency virus in vitro.
Year : 2007
Volume : 51
Issue : 6
First Page : 2143
Last Page : 2155
Authors : Amano M, Koh Y, Das D, Li J, Leschenko S, Wang YF, Boross PI, Weber IT, Ghosh AK, Mitsuya H.
Abstract : We designed, synthesized, and identified GRL-98065, a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) containing the structure-based designed privileged cyclic ether-derived nonpeptide P2 ligand, 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane (bis-THF), and a sulfonamide isostere, which is highly potent against laboratory HIV-1 strains and primary clinical isolates (50% effective concentration [EC(50)], 0.0002 to 0.0005 microM) with minimal cytotoxicity (50% cytotoxicity, 35.7 microM in CD4(+) MT-2 cells). GRL-98065 blocked the infectivity and replication of each of the HIV-1(NL4-3) variants exposed to and selected by up to a 5 microM concentration of saquinavir, indinavir, nelfinavir, or ritonavir and a 1 microM concentration of lopinavir or atazanavir (EC(50), 0.0015 to 0.0075 microM), although it was less active against HIV-1(NL4-3) selected by amprenavir (EC(50), 0.032 microM). GRL-98065 was also potent against multiple-PI-resistant clinical HIV-1 variants isolated from patients who had no response to existing antiviral regimens after having received a variety of antiviral agents, HIV-1 isolates of various subtypes, and HIV-2 isolates examined. Structural analyses revealed that the close contact of GRL-98065 with the main chain of the protease active-site amino acids (Asp29 and Asp30) is important for its potency and wide-spectrum activity against multiple-PI-resistant HIV-1 variants. The present data demonstrate that the privileged nonpeptide P2 ligand, bis-THF, is critical for the binding of GRL-98065 to the HIV protease substrate binding site and that this scaffold can confer highly potent antiviral activity against a wide spectrum of HIV isolates.
|
Antiviral activity against wild type HIV1 ERS104prc X4 in phytohemagglutininin-activated PBMCs assessed as inhibition of p24 Gag protein expression by MTT assay
|
Human immunodeficiency virus 1
|
15.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : A novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI), GRL-98065, is potent against multiple-PI-resistant human immunodeficiency virus in vitro.
Year : 2007
Volume : 51
Issue : 6
First Page : 2143
Last Page : 2155
Authors : Amano M, Koh Y, Das D, Li J, Leschenko S, Wang YF, Boross PI, Weber IT, Ghosh AK, Mitsuya H.
Abstract : We designed, synthesized, and identified GRL-98065, a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) containing the structure-based designed privileged cyclic ether-derived nonpeptide P2 ligand, 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane (bis-THF), and a sulfonamide isostere, which is highly potent against laboratory HIV-1 strains and primary clinical isolates (50% effective concentration [EC(50)], 0.0002 to 0.0005 microM) with minimal cytotoxicity (50% cytotoxicity, 35.7 microM in CD4(+) MT-2 cells). GRL-98065 blocked the infectivity and replication of each of the HIV-1(NL4-3) variants exposed to and selected by up to a 5 microM concentration of saquinavir, indinavir, nelfinavir, or ritonavir and a 1 microM concentration of lopinavir or atazanavir (EC(50), 0.0015 to 0.0075 microM), although it was less active against HIV-1(NL4-3) selected by amprenavir (EC(50), 0.032 microM). GRL-98065 was also potent against multiple-PI-resistant clinical HIV-1 variants isolated from patients who had no response to existing antiviral regimens after having received a variety of antiviral agents, HIV-1 isolates of various subtypes, and HIV-2 isolates examined. Structural analyses revealed that the close contact of GRL-98065 with the main chain of the protease active-site amino acids (Asp29 and Asp30) is important for its potency and wide-spectrum activity against multiple-PI-resistant HIV-1 variants. The present data demonstrate that the privileged nonpeptide P2 ligand, bis-THF, is critical for the binding of GRL-98065 to the HIV protease substrate binding site and that this scaffold can confer highly potent antiviral activity against a wide spectrum of HIV isolates.
|
Antiviral activity against HIV1 MDR/C X4 in phytohemagglutininin-activated PBMCs assessed as inhibition of p24 Gag protein expression by MTT assay
|
Human immunodeficiency virus 1
|
420.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : A novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI), GRL-98065, is potent against multiple-PI-resistant human immunodeficiency virus in vitro.
Year : 2007
Volume : 51
Issue : 6
First Page : 2143
Last Page : 2155
Authors : Amano M, Koh Y, Das D, Li J, Leschenko S, Wang YF, Boross PI, Weber IT, Ghosh AK, Mitsuya H.
Abstract : We designed, synthesized, and identified GRL-98065, a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) containing the structure-based designed privileged cyclic ether-derived nonpeptide P2 ligand, 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane (bis-THF), and a sulfonamide isostere, which is highly potent against laboratory HIV-1 strains and primary clinical isolates (50% effective concentration [EC(50)], 0.0002 to 0.0005 microM) with minimal cytotoxicity (50% cytotoxicity, 35.7 microM in CD4(+) MT-2 cells). GRL-98065 blocked the infectivity and replication of each of the HIV-1(NL4-3) variants exposed to and selected by up to a 5 microM concentration of saquinavir, indinavir, nelfinavir, or ritonavir and a 1 microM concentration of lopinavir or atazanavir (EC(50), 0.0015 to 0.0075 microM), although it was less active against HIV-1(NL4-3) selected by amprenavir (EC(50), 0.032 microM). GRL-98065 was also potent against multiple-PI-resistant clinical HIV-1 variants isolated from patients who had no response to existing antiviral regimens after having received a variety of antiviral agents, HIV-1 isolates of various subtypes, and HIV-2 isolates examined. Structural analyses revealed that the close contact of GRL-98065 with the main chain of the protease active-site amino acids (Asp29 and Asp30) is important for its potency and wide-spectrum activity against multiple-PI-resistant HIV-1 variants. The present data demonstrate that the privileged nonpeptide P2 ligand, bis-THF, is critical for the binding of GRL-98065 to the HIV protease substrate binding site and that this scaffold can confer highly potent antiviral activity against a wide spectrum of HIV isolates.
|
Antiviral activity against HIV1 MDR/G X4 in phytohemagglutininin-activated PBMCs assessed as inhibition of p24 Gag protein expression by MTT assay
|
Human immunodeficiency virus 1
|
370.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : A novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI), GRL-98065, is potent against multiple-PI-resistant human immunodeficiency virus in vitro.
Year : 2007
Volume : 51
Issue : 6
First Page : 2143
Last Page : 2155
Authors : Amano M, Koh Y, Das D, Li J, Leschenko S, Wang YF, Boross PI, Weber IT, Ghosh AK, Mitsuya H.
Abstract : We designed, synthesized, and identified GRL-98065, a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) containing the structure-based designed privileged cyclic ether-derived nonpeptide P2 ligand, 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane (bis-THF), and a sulfonamide isostere, which is highly potent against laboratory HIV-1 strains and primary clinical isolates (50% effective concentration [EC(50)], 0.0002 to 0.0005 microM) with minimal cytotoxicity (50% cytotoxicity, 35.7 microM in CD4(+) MT-2 cells). GRL-98065 blocked the infectivity and replication of each of the HIV-1(NL4-3) variants exposed to and selected by up to a 5 microM concentration of saquinavir, indinavir, nelfinavir, or ritonavir and a 1 microM concentration of lopinavir or atazanavir (EC(50), 0.0015 to 0.0075 microM), although it was less active against HIV-1(NL4-3) selected by amprenavir (EC(50), 0.032 microM). GRL-98065 was also potent against multiple-PI-resistant clinical HIV-1 variants isolated from patients who had no response to existing antiviral regimens after having received a variety of antiviral agents, HIV-1 isolates of various subtypes, and HIV-2 isolates examined. Structural analyses revealed that the close contact of GRL-98065 with the main chain of the protease active-site amino acids (Asp29 and Asp30) is important for its potency and wide-spectrum activity against multiple-PI-resistant HIV-1 variants. The present data demonstrate that the privileged nonpeptide P2 ligand, bis-THF, is critical for the binding of GRL-98065 to the HIV protease substrate binding site and that this scaffold can confer highly potent antiviral activity against a wide spectrum of HIV isolates.
|
Antiviral activity against HIV1 92UG029 X4 subtype A in phytohemagglutininin-activated PBMCs assessed as inhibition of p24 Gag protein expression by MTT assay
|
Human immunodeficiency virus 1
|
43.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : A novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI), GRL-98065, is potent against multiple-PI-resistant human immunodeficiency virus in vitro.
Year : 2007
Volume : 51
Issue : 6
First Page : 2143
Last Page : 2155
Authors : Amano M, Koh Y, Das D, Li J, Leschenko S, Wang YF, Boross PI, Weber IT, Ghosh AK, Mitsuya H.
Abstract : We designed, synthesized, and identified GRL-98065, a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) containing the structure-based designed privileged cyclic ether-derived nonpeptide P2 ligand, 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane (bis-THF), and a sulfonamide isostere, which is highly potent against laboratory HIV-1 strains and primary clinical isolates (50% effective concentration [EC(50)], 0.0002 to 0.0005 microM) with minimal cytotoxicity (50% cytotoxicity, 35.7 microM in CD4(+) MT-2 cells). GRL-98065 blocked the infectivity and replication of each of the HIV-1(NL4-3) variants exposed to and selected by up to a 5 microM concentration of saquinavir, indinavir, nelfinavir, or ritonavir and a 1 microM concentration of lopinavir or atazanavir (EC(50), 0.0015 to 0.0075 microM), although it was less active against HIV-1(NL4-3) selected by amprenavir (EC(50), 0.032 microM). GRL-98065 was also potent against multiple-PI-resistant clinical HIV-1 variants isolated from patients who had no response to existing antiviral regimens after having received a variety of antiviral agents, HIV-1 isolates of various subtypes, and HIV-2 isolates examined. Structural analyses revealed that the close contact of GRL-98065 with the main chain of the protease active-site amino acids (Asp29 and Asp30) is important for its potency and wide-spectrum activity against multiple-PI-resistant HIV-1 variants. The present data demonstrate that the privileged nonpeptide P2 ligand, bis-THF, is critical for the binding of GRL-98065 to the HIV protease substrate binding site and that this scaffold can confer highly potent antiviral activity against a wide spectrum of HIV isolates.
|
Antiviral activity against HIV1 92UG037 subtype A R5 in phytohemagglutininin-activated PBMCs assessed as inhibition of p24 Gag protein expression by MTT assay
|
Human immunodeficiency virus 1
|
56.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : A novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI), GRL-98065, is potent against multiple-PI-resistant human immunodeficiency virus in vitro.
Year : 2007
Volume : 51
Issue : 6
First Page : 2143
Last Page : 2155
Authors : Amano M, Koh Y, Das D, Li J, Leschenko S, Wang YF, Boross PI, Weber IT, Ghosh AK, Mitsuya H.
Abstract : We designed, synthesized, and identified GRL-98065, a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) containing the structure-based designed privileged cyclic ether-derived nonpeptide P2 ligand, 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane (bis-THF), and a sulfonamide isostere, which is highly potent against laboratory HIV-1 strains and primary clinical isolates (50% effective concentration [EC(50)], 0.0002 to 0.0005 microM) with minimal cytotoxicity (50% cytotoxicity, 35.7 microM in CD4(+) MT-2 cells). GRL-98065 blocked the infectivity and replication of each of the HIV-1(NL4-3) variants exposed to and selected by up to a 5 microM concentration of saquinavir, indinavir, nelfinavir, or ritonavir and a 1 microM concentration of lopinavir or atazanavir (EC(50), 0.0015 to 0.0075 microM), although it was less active against HIV-1(NL4-3) selected by amprenavir (EC(50), 0.032 microM). GRL-98065 was also potent against multiple-PI-resistant clinical HIV-1 variants isolated from patients who had no response to existing antiviral regimens after having received a variety of antiviral agents, HIV-1 isolates of various subtypes, and HIV-2 isolates examined. Structural analyses revealed that the close contact of GRL-98065 with the main chain of the protease active-site amino acids (Asp29 and Asp30) is important for its potency and wide-spectrum activity against multiple-PI-resistant HIV-1 variants. The present data demonstrate that the privileged nonpeptide P2 ligand, bis-THF, is critical for the binding of GRL-98065 to the HIV protease substrate binding site and that this scaffold can confer highly potent antiviral activity against a wide spectrum of HIV isolates.
|
Antiviral activity against HIV1 BaL R5 subtype B in phytohemagglutininin-activated PBMCs assessed as inhibition of p24 Gag protein expression by MTT assay
|
Human immunodeficiency virus 1
|
18.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : A novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI), GRL-98065, is potent against multiple-PI-resistant human immunodeficiency virus in vitro.
Year : 2007
Volume : 51
Issue : 6
First Page : 2143
Last Page : 2155
Authors : Amano M, Koh Y, Das D, Li J, Leschenko S, Wang YF, Boross PI, Weber IT, Ghosh AK, Mitsuya H.
Abstract : We designed, synthesized, and identified GRL-98065, a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) containing the structure-based designed privileged cyclic ether-derived nonpeptide P2 ligand, 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane (bis-THF), and a sulfonamide isostere, which is highly potent against laboratory HIV-1 strains and primary clinical isolates (50% effective concentration [EC(50)], 0.0002 to 0.0005 microM) with minimal cytotoxicity (50% cytotoxicity, 35.7 microM in CD4(+) MT-2 cells). GRL-98065 blocked the infectivity and replication of each of the HIV-1(NL4-3) variants exposed to and selected by up to a 5 microM concentration of saquinavir, indinavir, nelfinavir, or ritonavir and a 1 microM concentration of lopinavir or atazanavir (EC(50), 0.0015 to 0.0075 microM), although it was less active against HIV-1(NL4-3) selected by amprenavir (EC(50), 0.032 microM). GRL-98065 was also potent against multiple-PI-resistant clinical HIV-1 variants isolated from patients who had no response to existing antiviral regimens after having received a variety of antiviral agents, HIV-1 isolates of various subtypes, and HIV-2 isolates examined. Structural analyses revealed that the close contact of GRL-98065 with the main chain of the protease active-site amino acids (Asp29 and Asp30) is important for its potency and wide-spectrum activity against multiple-PI-resistant HIV-1 variants. The present data demonstrate that the privileged nonpeptide P2 ligand, bis-THF, is critical for the binding of GRL-98065 to the HIV protease substrate binding site and that this scaffold can confer highly potent antiviral activity against a wide spectrum of HIV isolates.
|
Antiviral activity against HIV1 97ZA003 R5 subtype C in phytohemagglutininin-activated PBMCs assessed as inhibition of p24 Gag protein expression by MTT assay
|
Human immunodeficiency virus 1
|
37.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : A novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI), GRL-98065, is potent against multiple-PI-resistant human immunodeficiency virus in vitro.
Year : 2007
Volume : 51
Issue : 6
First Page : 2143
Last Page : 2155
Authors : Amano M, Koh Y, Das D, Li J, Leschenko S, Wang YF, Boross PI, Weber IT, Ghosh AK, Mitsuya H.
Abstract : We designed, synthesized, and identified GRL-98065, a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) containing the structure-based designed privileged cyclic ether-derived nonpeptide P2 ligand, 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane (bis-THF), and a sulfonamide isostere, which is highly potent against laboratory HIV-1 strains and primary clinical isolates (50% effective concentration [EC(50)], 0.0002 to 0.0005 microM) with minimal cytotoxicity (50% cytotoxicity, 35.7 microM in CD4(+) MT-2 cells). GRL-98065 blocked the infectivity and replication of each of the HIV-1(NL4-3) variants exposed to and selected by up to a 5 microM concentration of saquinavir, indinavir, nelfinavir, or ritonavir and a 1 microM concentration of lopinavir or atazanavir (EC(50), 0.0015 to 0.0075 microM), although it was less active against HIV-1(NL4-3) selected by amprenavir (EC(50), 0.032 microM). GRL-98065 was also potent against multiple-PI-resistant clinical HIV-1 variants isolated from patients who had no response to existing antiviral regimens after having received a variety of antiviral agents, HIV-1 isolates of various subtypes, and HIV-2 isolates examined. Structural analyses revealed that the close contact of GRL-98065 with the main chain of the protease active-site amino acids (Asp29 and Asp30) is important for its potency and wide-spectrum activity against multiple-PI-resistant HIV-1 variants. The present data demonstrate that the privileged nonpeptide P2 ligand, bis-THF, is critical for the binding of GRL-98065 to the HIV protease substrate binding site and that this scaffold can confer highly potent antiviral activity against a wide spectrum of HIV isolates.
|
Antiviral activity against HIV1 92TH019 R5 subtype E in phytohemagglutininin-activated PBMCs assessed as inhibition of p24 Gag protein expression by MTT assay
|
Human immunodeficiency virus 1
|
29.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : A novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI), GRL-98065, is potent against multiple-PI-resistant human immunodeficiency virus in vitro.
Year : 2007
Volume : 51
Issue : 6
First Page : 2143
Last Page : 2155
Authors : Amano M, Koh Y, Das D, Li J, Leschenko S, Wang YF, Boross PI, Weber IT, Ghosh AK, Mitsuya H.
Abstract : We designed, synthesized, and identified GRL-98065, a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) containing the structure-based designed privileged cyclic ether-derived nonpeptide P2 ligand, 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane (bis-THF), and a sulfonamide isostere, which is highly potent against laboratory HIV-1 strains and primary clinical isolates (50% effective concentration [EC(50)], 0.0002 to 0.0005 microM) with minimal cytotoxicity (50% cytotoxicity, 35.7 microM in CD4(+) MT-2 cells). GRL-98065 blocked the infectivity and replication of each of the HIV-1(NL4-3) variants exposed to and selected by up to a 5 microM concentration of saquinavir, indinavir, nelfinavir, or ritonavir and a 1 microM concentration of lopinavir or atazanavir (EC(50), 0.0015 to 0.0075 microM), although it was less active against HIV-1(NL4-3) selected by amprenavir (EC(50), 0.032 microM). GRL-98065 was also potent against multiple-PI-resistant clinical HIV-1 variants isolated from patients who had no response to existing antiviral regimens after having received a variety of antiviral agents, HIV-1 isolates of various subtypes, and HIV-2 isolates examined. Structural analyses revealed that the close contact of GRL-98065 with the main chain of the protease active-site amino acids (Asp29 and Asp30) is important for its potency and wide-spectrum activity against multiple-PI-resistant HIV-1 variants. The present data demonstrate that the privileged nonpeptide P2 ligand, bis-THF, is critical for the binding of GRL-98065 to the HIV protease substrate binding site and that this scaffold can confer highly potent antiviral activity against a wide spectrum of HIV isolates.
|
Inhibition of wild-type HIV1 BH10 protease expressed in Escherichia coli by spectrophotometric assay
|
Human immunodeficiency virus 1
|
0.07
nM
|
|
Journal : J. Med. Chem.
Title : Inorganic polyhedral metallacarborane inhibitors of HIV protease: a new approach to overcoming antiviral resistance.
Year : 2008
Volume : 51
Issue : 15
First Page : 4839
Last Page : 4843
Authors : Kozísek M, Cígler P, Lepsík M, Fanfrlík J, Rezácová P, Brynda J, Pokorná J, Plesek J, Grüner B, Grantz Sasková K, Václavíková J, Král V, Konvalinka J.
Abstract : HIV protease (PR) is a prime target for rational anti-HIV drug design. We have previously identified icosahedral metallacarboranes as a novel class of nonpeptidic protease inhibitors. Now we show that substituted metallacarboranes are potent and specific competitive inhibitors of drug-resistant HIV PRs prepared either by site-directed mutagenesis or cloned from HIV-positive patients. Molecular modeling explains the inhibition profile of metallacarboranes by their unconventional binding mode.
|
Inhibition of HIV1 recombinant protease D30N/N88D mutant expressed in Escherichia coli by spectrophotometric assay
|
Human immunodeficiency virus 1
|
18.0
nM
|
|
Journal : J. Med. Chem.
Title : Inorganic polyhedral metallacarborane inhibitors of HIV protease: a new approach to overcoming antiviral resistance.
Year : 2008
Volume : 51
Issue : 15
First Page : 4839
Last Page : 4843
Authors : Kozísek M, Cígler P, Lepsík M, Fanfrlík J, Rezácová P, Brynda J, Pokorná J, Plesek J, Grüner B, Grantz Sasková K, Václavíková J, Král V, Konvalinka J.
Abstract : HIV protease (PR) is a prime target for rational anti-HIV drug design. We have previously identified icosahedral metallacarboranes as a novel class of nonpeptidic protease inhibitors. Now we show that substituted metallacarboranes are potent and specific competitive inhibitors of drug-resistant HIV PRs prepared either by site-directed mutagenesis or cloned from HIV-positive patients. Molecular modeling explains the inhibition profile of metallacarboranes by their unconventional binding mode.
|
Inhibition of HIV1 recombinant protease M46I/A71V/V82T/I84V mutant expressed in Escherichia coli by spectrophotometric assay
|
Human immunodeficiency virus 1
|
3.8
nM
|
|
Journal : J. Med. Chem.
Title : Inorganic polyhedral metallacarborane inhibitors of HIV protease: a new approach to overcoming antiviral resistance.
Year : 2008
Volume : 51
Issue : 15
First Page : 4839
Last Page : 4843
Authors : Kozísek M, Cígler P, Lepsík M, Fanfrlík J, Rezácová P, Brynda J, Pokorná J, Plesek J, Grüner B, Grantz Sasková K, Václavíková J, Král V, Konvalinka J.
Abstract : HIV protease (PR) is a prime target for rational anti-HIV drug design. We have previously identified icosahedral metallacarboranes as a novel class of nonpeptidic protease inhibitors. Now we show that substituted metallacarboranes are potent and specific competitive inhibitors of drug-resistant HIV PRs prepared either by site-directed mutagenesis or cloned from HIV-positive patients. Molecular modeling explains the inhibition profile of metallacarboranes by their unconventional binding mode.
|
Inhibition of HIV1 recombinant protease A71V/V82T/I84V mutant expressed in Escherichia coli by spectrophotometric assay
|
Human immunodeficiency virus 1
|
3.2
nM
|
|
Journal : J. Med. Chem.
Title : Inorganic polyhedral metallacarborane inhibitors of HIV protease: a new approach to overcoming antiviral resistance.
Year : 2008
Volume : 51
Issue : 15
First Page : 4839
Last Page : 4843
Authors : Kozísek M, Cígler P, Lepsík M, Fanfrlík J, Rezácová P, Brynda J, Pokorná J, Plesek J, Grüner B, Grantz Sasková K, Václavíková J, Král V, Konvalinka J.
Abstract : HIV protease (PR) is a prime target for rational anti-HIV drug design. We have previously identified icosahedral metallacarboranes as a novel class of nonpeptidic protease inhibitors. Now we show that substituted metallacarboranes are potent and specific competitive inhibitors of drug-resistant HIV PRs prepared either by site-directed mutagenesis or cloned from HIV-positive patients. Molecular modeling explains the inhibition profile of metallacarboranes by their unconventional binding mode.
|
Inhibition of HIV1 recombinant protease V32I/I47A mutant expressed in Escherichia coli by spectrophotometric assay
|
Human immunodeficiency virus 1
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : Inorganic polyhedral metallacarborane inhibitors of HIV protease: a new approach to overcoming antiviral resistance.
Year : 2008
Volume : 51
Issue : 15
First Page : 4839
Last Page : 4843
Authors : Kozísek M, Cígler P, Lepsík M, Fanfrlík J, Rezácová P, Brynda J, Pokorná J, Plesek J, Grüner B, Grantz Sasková K, Václavíková J, Král V, Konvalinka J.
Abstract : HIV protease (PR) is a prime target for rational anti-HIV drug design. We have previously identified icosahedral metallacarboranes as a novel class of nonpeptidic protease inhibitors. Now we show that substituted metallacarboranes are potent and specific competitive inhibitors of drug-resistant HIV PRs prepared either by site-directed mutagenesis or cloned from HIV-positive patients. Molecular modeling explains the inhibition profile of metallacarboranes by their unconventional binding mode.
|
Inhibition of HIV1 recombinant protease L10I/I15V/E35D/N37S/R41K/I62V/L63P/A71V/G73S/L90M mutant expressed in Escherichia coli by spectrophotometric assay
|
Human immunodeficiency virus 1
|
2.1
nM
|
|
Journal : J. Med. Chem.
Title : Inorganic polyhedral metallacarborane inhibitors of HIV protease: a new approach to overcoming antiviral resistance.
Year : 2008
Volume : 51
Issue : 15
First Page : 4839
Last Page : 4843
Authors : Kozísek M, Cígler P, Lepsík M, Fanfrlík J, Rezácová P, Brynda J, Pokorná J, Plesek J, Grüner B, Grantz Sasková K, Václavíková J, Král V, Konvalinka J.
Abstract : HIV protease (PR) is a prime target for rational anti-HIV drug design. We have previously identified icosahedral metallacarboranes as a novel class of nonpeptidic protease inhibitors. Now we show that substituted metallacarboranes are potent and specific competitive inhibitors of drug-resistant HIV PRs prepared either by site-directed mutagenesis or cloned from HIV-positive patients. Molecular modeling explains the inhibition profile of metallacarboranes by their unconventional binding mode.
|
Inhibition of HIV1 recombinant protease L10I/L24I/L33F/M46L/154V/L63P/A71V/V82A/I84V mutant expressed in Escherichia coli by spectrophotometric assay
|
Human immunodeficiency virus 1
|
130.0
nM
|
|
Journal : J. Med. Chem.
Title : Inorganic polyhedral metallacarborane inhibitors of HIV protease: a new approach to overcoming antiviral resistance.
Year : 2008
Volume : 51
Issue : 15
First Page : 4839
Last Page : 4843
Authors : Kozísek M, Cígler P, Lepsík M, Fanfrlík J, Rezácová P, Brynda J, Pokorná J, Plesek J, Grüner B, Grantz Sasková K, Václavíková J, Král V, Konvalinka J.
Abstract : HIV protease (PR) is a prime target for rational anti-HIV drug design. We have previously identified icosahedral metallacarboranes as a novel class of nonpeptidic protease inhibitors. Now we show that substituted metallacarboranes are potent and specific competitive inhibitors of drug-resistant HIV PRs prepared either by site-directed mutagenesis or cloned from HIV-positive patients. Molecular modeling explains the inhibition profile of metallacarboranes by their unconventional binding mode.
|
Inhibition of HIV1 recombinant protease L10F/L19I/K20R/L33F/E35D/M36I/R41K/F53L/I54V/L63P/H69K/A71V/T74P/I84V/L89M/L90M/I93L mutant expressed in Escherichia coli by spectrophotometric assay
|
Human immunodeficiency virus 1
|
32.0
nM
|
|
Journal : J. Med. Chem.
Title : Inorganic polyhedral metallacarborane inhibitors of HIV protease: a new approach to overcoming antiviral resistance.
Year : 2008
Volume : 51
Issue : 15
First Page : 4839
Last Page : 4843
Authors : Kozísek M, Cígler P, Lepsík M, Fanfrlík J, Rezácová P, Brynda J, Pokorná J, Plesek J, Grüner B, Grantz Sasková K, Václavíková J, Král V, Konvalinka J.
Abstract : HIV protease (PR) is a prime target for rational anti-HIV drug design. We have previously identified icosahedral metallacarboranes as a novel class of nonpeptidic protease inhibitors. Now we show that substituted metallacarboranes are potent and specific competitive inhibitors of drug-resistant HIV PRs prepared either by site-directed mutagenesis or cloned from HIV-positive patients. Molecular modeling explains the inhibition profile of metallacarboranes by their unconventional binding mode.
|
Ratio of Ki for HIV1 recombinant protease D30N/N88D mutant to Ki for wild-type HIV1 BH10 protease
|
Human immunodeficiency virus 1
|
260.0
nM
|
|
Journal : J. Med. Chem.
Title : Inorganic polyhedral metallacarborane inhibitors of HIV protease: a new approach to overcoming antiviral resistance.
Year : 2008
Volume : 51
Issue : 15
First Page : 4839
Last Page : 4843
Authors : Kozísek M, Cígler P, Lepsík M, Fanfrlík J, Rezácová P, Brynda J, Pokorná J, Plesek J, Grüner B, Grantz Sasková K, Václavíková J, Král V, Konvalinka J.
Abstract : HIV protease (PR) is a prime target for rational anti-HIV drug design. We have previously identified icosahedral metallacarboranes as a novel class of nonpeptidic protease inhibitors. Now we show that substituted metallacarboranes are potent and specific competitive inhibitors of drug-resistant HIV PRs prepared either by site-directed mutagenesis or cloned from HIV-positive patients. Molecular modeling explains the inhibition profile of metallacarboranes by their unconventional binding mode.
|
Ratio of Ki for HIV1 recombinant protease M46I/A71V/V82T/I84V mutant to Ki for wild-type HIV1 BH10 protease
|
Human immunodeficiency virus 1
|
54.0
nM
|
|
Journal : J. Med. Chem.
Title : Inorganic polyhedral metallacarborane inhibitors of HIV protease: a new approach to overcoming antiviral resistance.
Year : 2008
Volume : 51
Issue : 15
First Page : 4839
Last Page : 4843
Authors : Kozísek M, Cígler P, Lepsík M, Fanfrlík J, Rezácová P, Brynda J, Pokorná J, Plesek J, Grüner B, Grantz Sasková K, Václavíková J, Král V, Konvalinka J.
Abstract : HIV protease (PR) is a prime target for rational anti-HIV drug design. We have previously identified icosahedral metallacarboranes as a novel class of nonpeptidic protease inhibitors. Now we show that substituted metallacarboranes are potent and specific competitive inhibitors of drug-resistant HIV PRs prepared either by site-directed mutagenesis or cloned from HIV-positive patients. Molecular modeling explains the inhibition profile of metallacarboranes by their unconventional binding mode.
|
Ratio of Ki for HIV1 recombinant protease A71V/V82T/I84V mutant to Ki for wild-type HIV1 BH10 protease
|
Human immunodeficiency virus 1
|
46.0
nM
|
|
Journal : J. Med. Chem.
Title : Inorganic polyhedral metallacarborane inhibitors of HIV protease: a new approach to overcoming antiviral resistance.
Year : 2008
Volume : 51
Issue : 15
First Page : 4839
Last Page : 4843
Authors : Kozísek M, Cígler P, Lepsík M, Fanfrlík J, Rezácová P, Brynda J, Pokorná J, Plesek J, Grüner B, Grantz Sasková K, Václavíková J, Král V, Konvalinka J.
Abstract : HIV protease (PR) is a prime target for rational anti-HIV drug design. We have previously identified icosahedral metallacarboranes as a novel class of nonpeptidic protease inhibitors. Now we show that substituted metallacarboranes are potent and specific competitive inhibitors of drug-resistant HIV PRs prepared either by site-directed mutagenesis or cloned from HIV-positive patients. Molecular modeling explains the inhibition profile of metallacarboranes by their unconventional binding mode.
|
Ratio of Ki for HIV1 recombinant protease V32I/I47A mutant to Ki for wild-type HIV1 BH10 protease
|
Human immunodeficiency virus 1
|
140.0
nM
|
|
Journal : J. Med. Chem.
Title : Inorganic polyhedral metallacarborane inhibitors of HIV protease: a new approach to overcoming antiviral resistance.
Year : 2008
Volume : 51
Issue : 15
First Page : 4839
Last Page : 4843
Authors : Kozísek M, Cígler P, Lepsík M, Fanfrlík J, Rezácová P, Brynda J, Pokorná J, Plesek J, Grüner B, Grantz Sasková K, Václavíková J, Král V, Konvalinka J.
Abstract : HIV protease (PR) is a prime target for rational anti-HIV drug design. We have previously identified icosahedral metallacarboranes as a novel class of nonpeptidic protease inhibitors. Now we show that substituted metallacarboranes are potent and specific competitive inhibitors of drug-resistant HIV PRs prepared either by site-directed mutagenesis or cloned from HIV-positive patients. Molecular modeling explains the inhibition profile of metallacarboranes by their unconventional binding mode.
|
Ratio of Ki for HIV1 recombinant protease L10I/I15V/E35D/N37S/R41K/I62V/L63P/A71V/G73S/L90M mutant to Ki for wild-type HIV1 BH10 protease
|
Human immunodeficiency virus 1
|
30.0
nM
|
|
Journal : J. Med. Chem.
Title : Inorganic polyhedral metallacarborane inhibitors of HIV protease: a new approach to overcoming antiviral resistance.
Year : 2008
Volume : 51
Issue : 15
First Page : 4839
Last Page : 4843
Authors : Kozísek M, Cígler P, Lepsík M, Fanfrlík J, Rezácová P, Brynda J, Pokorná J, Plesek J, Grüner B, Grantz Sasková K, Václavíková J, Král V, Konvalinka J.
Abstract : HIV protease (PR) is a prime target for rational anti-HIV drug design. We have previously identified icosahedral metallacarboranes as a novel class of nonpeptidic protease inhibitors. Now we show that substituted metallacarboranes are potent and specific competitive inhibitors of drug-resistant HIV PRs prepared either by site-directed mutagenesis or cloned from HIV-positive patients. Molecular modeling explains the inhibition profile of metallacarboranes by their unconventional binding mode.
|
Ratio of Ki for HIV1 recombinant protease L10F/L19I/K20R/L33F/E35D/M36I/R41K/F53L/I54V/L63P/H69K/A71V/T74P/I84V/L89M/L90M/I93L mutant to Ki for wild-type HIV1 BH10 protease
|
Human immunodeficiency virus 1
|
450.0
nM
|
|
Journal : J. Med. Chem.
Title : Inorganic polyhedral metallacarborane inhibitors of HIV protease: a new approach to overcoming antiviral resistance.
Year : 2008
Volume : 51
Issue : 15
First Page : 4839
Last Page : 4843
Authors : Kozísek M, Cígler P, Lepsík M, Fanfrlík J, Rezácová P, Brynda J, Pokorná J, Plesek J, Grüner B, Grantz Sasková K, Václavíková J, Král V, Konvalinka J.
Abstract : HIV protease (PR) is a prime target for rational anti-HIV drug design. We have previously identified icosahedral metallacarboranes as a novel class of nonpeptidic protease inhibitors. Now we show that substituted metallacarboranes are potent and specific competitive inhibitors of drug-resistant HIV PRs prepared either by site-directed mutagenesis or cloned from HIV-positive patients. Molecular modeling explains the inhibition profile of metallacarboranes by their unconventional binding mode.
|
Antiviral activity against HIV1 3B infected in human HOG.R5 cells after 4 days
|
Human immunodeficiency virus 1
|
90.0
nM
|
|
Journal : J. Nat. Prod.
Title : New 3-O-acyl betulinic acids from Strychnos vanprukii Craib.
Year : 2004
Volume : 67
Issue : 6
First Page : 994
Last Page : 998
Authors : Nguyen QC, Nguyen VH, Santarsiero BD, Mesecar AD, Nguyen MC, Soejarto DD, Pezzuto JM, Fong HH, Tan GT.
Abstract : Three new betulinic acid derivatives, 3beta-O-trans-feruloylbetulinic acid (1), 3beta-O-cis-feruloylbetulinic acid (2), and 3beta-O-cis-coumaroylbetulinic acid (4), along with two known triterpenes, 3beta-O-trans-coumaroylbetulinic acid (3) and ursolic acid (6) were isolated from the leaves and twigs of Strychnos vanprukiiCraib. All isolates showed moderate anti-HIV activity with IC50 values ranging from 3 to 7 microg/mL (5 to 15 microM) in an indicator cell line for HIV infectivity. The structures of the new isolates were elucidated by spectroscopic techniques including 1D and 2D NMR spectroscopy. In addition, the structure of 1 was confirmed by X-ray crystallography.
|
Antiviral activity against HIV1 NL4-3 infected in human MT4 cells assessed as reduction in virus-induced cytopathic effect after 5 days by MTT assay
|
Human immunodeficiency virus 1
|
18.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro selection and characterization of human immunodeficiency virus type 2 with decreased susceptibility to lopinavir.
Year : 2007
Volume : 51
Issue : 9
First Page : 3075
Last Page : 3080
Authors : Masse S, Lu X, Dekhtyar T, Lu L, Koev G, Gao F, Mo H, Kempf D, Bernstein B, Hanna GJ, Molla A.
Abstract : Lopinavir (LPV)-ritonavir has demonstrated durable antiviral activity in human immunodeficiency virus type 1 (HIV-1)-infected antiretroviral-naïve and protease inhibitor (PI)-experienced patients. However, information on LPV activity against HIV-2 and the patterns of mutations in HIV-2 in response to selection by LPV is limited. The activity of LPV against three strains of HIV-2 was assessed and compared to activity against a reference HIV-1 strain. LPV demonstrated activity similar to that observed against HIV-1 in two HIV-2 strains (HIV-2(MS) and HIV-2(CBL-23)) tested. On the other hand, approximately 10-fold-reduced susceptibility was observed with the third HIV-2 strain, HIV-2(CDC310319). Passage of HIV-2(MS) with increasing concentrations of LPV selected mutations V47A and D17N in the HIV-2 protease gene. The introduction of both 17N and 47A either individually or together into HIV-2(ROD) molecular infectious clones showed that the single V47A substitution in HIV-2 resulted in a substantial reduction in susceptibility to LPV. In contrast, this mutant retained wild-type susceptibility to other PIs and appeared to be hypersusceptible to atazanavir and saquinavir.
|
Antiviral activity against HIV2 MS infected in human MT4 cells assessed as reduction in virus-induced cytopathic effect after 5 days by MTT assay
|
Human immunodeficiency virus 2
|
48.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro selection and characterization of human immunodeficiency virus type 2 with decreased susceptibility to lopinavir.
Year : 2007
Volume : 51
Issue : 9
First Page : 3075
Last Page : 3080
Authors : Masse S, Lu X, Dekhtyar T, Lu L, Koev G, Gao F, Mo H, Kempf D, Bernstein B, Hanna GJ, Molla A.
Abstract : Lopinavir (LPV)-ritonavir has demonstrated durable antiviral activity in human immunodeficiency virus type 1 (HIV-1)-infected antiretroviral-naïve and protease inhibitor (PI)-experienced patients. However, information on LPV activity against HIV-2 and the patterns of mutations in HIV-2 in response to selection by LPV is limited. The activity of LPV against three strains of HIV-2 was assessed and compared to activity against a reference HIV-1 strain. LPV demonstrated activity similar to that observed against HIV-1 in two HIV-2 strains (HIV-2(MS) and HIV-2(CBL-23)) tested. On the other hand, approximately 10-fold-reduced susceptibility was observed with the third HIV-2 strain, HIV-2(CDC310319). Passage of HIV-2(MS) with increasing concentrations of LPV selected mutations V47A and D17N in the HIV-2 protease gene. The introduction of both 17N and 47A either individually or together into HIV-2(ROD) molecular infectious clones showed that the single V47A substitution in HIV-2 resulted in a substantial reduction in susceptibility to LPV. In contrast, this mutant retained wild-type susceptibility to other PIs and appeared to be hypersusceptible to atazanavir and saquinavir.
|
Antiviral activity against HIV2 CBL-23 infected in human PBMC assessed as inhibition of virus production after 5 days by Lenti-RT activity assay
|
Human immunodeficiency virus 2
|
83.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro selection and characterization of human immunodeficiency virus type 2 with decreased susceptibility to lopinavir.
Year : 2007
Volume : 51
Issue : 9
First Page : 3075
Last Page : 3080
Authors : Masse S, Lu X, Dekhtyar T, Lu L, Koev G, Gao F, Mo H, Kempf D, Bernstein B, Hanna GJ, Molla A.
Abstract : Lopinavir (LPV)-ritonavir has demonstrated durable antiviral activity in human immunodeficiency virus type 1 (HIV-1)-infected antiretroviral-naïve and protease inhibitor (PI)-experienced patients. However, information on LPV activity against HIV-2 and the patterns of mutations in HIV-2 in response to selection by LPV is limited. The activity of LPV against three strains of HIV-2 was assessed and compared to activity against a reference HIV-1 strain. LPV demonstrated activity similar to that observed against HIV-1 in two HIV-2 strains (HIV-2(MS) and HIV-2(CBL-23)) tested. On the other hand, approximately 10-fold-reduced susceptibility was observed with the third HIV-2 strain, HIV-2(CDC310319). Passage of HIV-2(MS) with increasing concentrations of LPV selected mutations V47A and D17N in the HIV-2 protease gene. The introduction of both 17N and 47A either individually or together into HIV-2(ROD) molecular infectious clones showed that the single V47A substitution in HIV-2 resulted in a substantial reduction in susceptibility to LPV. In contrast, this mutant retained wild-type susceptibility to other PIs and appeared to be hypersusceptible to atazanavir and saquinavir.
|
Antiviral activity against HIV2 CDC310319 isolate infected in human PBMC assessed as inhibition of virus production after 5 days by Lenti-RT activity assay
|
Human immunodeficiency virus 2
|
389.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro selection and characterization of human immunodeficiency virus type 2 with decreased susceptibility to lopinavir.
Year : 2007
Volume : 51
Issue : 9
First Page : 3075
Last Page : 3080
Authors : Masse S, Lu X, Dekhtyar T, Lu L, Koev G, Gao F, Mo H, Kempf D, Bernstein B, Hanna GJ, Molla A.
Abstract : Lopinavir (LPV)-ritonavir has demonstrated durable antiviral activity in human immunodeficiency virus type 1 (HIV-1)-infected antiretroviral-naïve and protease inhibitor (PI)-experienced patients. However, information on LPV activity against HIV-2 and the patterns of mutations in HIV-2 in response to selection by LPV is limited. The activity of LPV against three strains of HIV-2 was assessed and compared to activity against a reference HIV-1 strain. LPV demonstrated activity similar to that observed against HIV-1 in two HIV-2 strains (HIV-2(MS) and HIV-2(CBL-23)) tested. On the other hand, approximately 10-fold-reduced susceptibility was observed with the third HIV-2 strain, HIV-2(CDC310319). Passage of HIV-2(MS) with increasing concentrations of LPV selected mutations V47A and D17N in the HIV-2 protease gene. The introduction of both 17N and 47A either individually or together into HIV-2(ROD) molecular infectious clones showed that the single V47A substitution in HIV-2 resulted in a substantial reduction in susceptibility to LPV. In contrast, this mutant retained wild-type susceptibility to other PIs and appeared to be hypersusceptible to atazanavir and saquinavir.
|
Antiviral activity against wild type HIV2 ROD infected in human CEM cells assessed as inhibition of virus production after 7 days by Lenti-RT activity assay
|
Human immunodeficiency virus 2
|
281.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro selection and characterization of human immunodeficiency virus type 2 with decreased susceptibility to lopinavir.
Year : 2007
Volume : 51
Issue : 9
First Page : 3075
Last Page : 3080
Authors : Masse S, Lu X, Dekhtyar T, Lu L, Koev G, Gao F, Mo H, Kempf D, Bernstein B, Hanna GJ, Molla A.
Abstract : Lopinavir (LPV)-ritonavir has demonstrated durable antiviral activity in human immunodeficiency virus type 1 (HIV-1)-infected antiretroviral-naïve and protease inhibitor (PI)-experienced patients. However, information on LPV activity against HIV-2 and the patterns of mutations in HIV-2 in response to selection by LPV is limited. The activity of LPV against three strains of HIV-2 was assessed and compared to activity against a reference HIV-1 strain. LPV demonstrated activity similar to that observed against HIV-1 in two HIV-2 strains (HIV-2(MS) and HIV-2(CBL-23)) tested. On the other hand, approximately 10-fold-reduced susceptibility was observed with the third HIV-2 strain, HIV-2(CDC310319). Passage of HIV-2(MS) with increasing concentrations of LPV selected mutations V47A and D17N in the HIV-2 protease gene. The introduction of both 17N and 47A either individually or together into HIV-2(ROD) molecular infectious clones showed that the single V47A substitution in HIV-2 resulted in a substantial reduction in susceptibility to LPV. In contrast, this mutant retained wild-type susceptibility to other PIs and appeared to be hypersusceptible to atazanavir and saquinavir.
|
Antiviral activity against HIV2 ROD with protease G17N mutation infected in human CEM cells assessed as inhibition of virus production after 7 days by Lenti-RT activity assay
|
Human immunodeficiency virus 2
|
199.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro selection and characterization of human immunodeficiency virus type 2 with decreased susceptibility to lopinavir.
Year : 2007
Volume : 51
Issue : 9
First Page : 3075
Last Page : 3080
Authors : Masse S, Lu X, Dekhtyar T, Lu L, Koev G, Gao F, Mo H, Kempf D, Bernstein B, Hanna GJ, Molla A.
Abstract : Lopinavir (LPV)-ritonavir has demonstrated durable antiviral activity in human immunodeficiency virus type 1 (HIV-1)-infected antiretroviral-naïve and protease inhibitor (PI)-experienced patients. However, information on LPV activity against HIV-2 and the patterns of mutations in HIV-2 in response to selection by LPV is limited. The activity of LPV against three strains of HIV-2 was assessed and compared to activity against a reference HIV-1 strain. LPV demonstrated activity similar to that observed against HIV-1 in two HIV-2 strains (HIV-2(MS) and HIV-2(CBL-23)) tested. On the other hand, approximately 10-fold-reduced susceptibility was observed with the third HIV-2 strain, HIV-2(CDC310319). Passage of HIV-2(MS) with increasing concentrations of LPV selected mutations V47A and D17N in the HIV-2 protease gene. The introduction of both 17N and 47A either individually or together into HIV-2(ROD) molecular infectious clones showed that the single V47A substitution in HIV-2 resulted in a substantial reduction in susceptibility to LPV. In contrast, this mutant retained wild-type susceptibility to other PIs and appeared to be hypersusceptible to atazanavir and saquinavir.
|
Antiviral activity against HIV2 ROD with protease V47A mutation infected in human CEM cells assessed as inhibition of virus production after 7 days by Lenti-RT activity assay
|
Human immunodeficiency virus 2
|
177.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro selection and characterization of human immunodeficiency virus type 2 with decreased susceptibility to lopinavir.
Year : 2007
Volume : 51
Issue : 9
First Page : 3075
Last Page : 3080
Authors : Masse S, Lu X, Dekhtyar T, Lu L, Koev G, Gao F, Mo H, Kempf D, Bernstein B, Hanna GJ, Molla A.
Abstract : Lopinavir (LPV)-ritonavir has demonstrated durable antiviral activity in human immunodeficiency virus type 1 (HIV-1)-infected antiretroviral-naïve and protease inhibitor (PI)-experienced patients. However, information on LPV activity against HIV-2 and the patterns of mutations in HIV-2 in response to selection by LPV is limited. The activity of LPV against three strains of HIV-2 was assessed and compared to activity against a reference HIV-1 strain. LPV demonstrated activity similar to that observed against HIV-1 in two HIV-2 strains (HIV-2(MS) and HIV-2(CBL-23)) tested. On the other hand, approximately 10-fold-reduced susceptibility was observed with the third HIV-2 strain, HIV-2(CDC310319). Passage of HIV-2(MS) with increasing concentrations of LPV selected mutations V47A and D17N in the HIV-2 protease gene. The introduction of both 17N and 47A either individually or together into HIV-2(ROD) molecular infectious clones showed that the single V47A substitution in HIV-2 resulted in a substantial reduction in susceptibility to LPV. In contrast, this mutant retained wild-type susceptibility to other PIs and appeared to be hypersusceptible to atazanavir and saquinavir.
|
Antiviral activity against HIV2 ROD with protease G17N/V47A mutation infected in human CEM cells assessed as inhibition of virus production after 7 days by Lenti-RT activity assay
|
Human immunodeficiency virus 2
|
100.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro selection and characterization of human immunodeficiency virus type 2 with decreased susceptibility to lopinavir.
Year : 2007
Volume : 51
Issue : 9
First Page : 3075
Last Page : 3080
Authors : Masse S, Lu X, Dekhtyar T, Lu L, Koev G, Gao F, Mo H, Kempf D, Bernstein B, Hanna GJ, Molla A.
Abstract : Lopinavir (LPV)-ritonavir has demonstrated durable antiviral activity in human immunodeficiency virus type 1 (HIV-1)-infected antiretroviral-naïve and protease inhibitor (PI)-experienced patients. However, information on LPV activity against HIV-2 and the patterns of mutations in HIV-2 in response to selection by LPV is limited. The activity of LPV against three strains of HIV-2 was assessed and compared to activity against a reference HIV-1 strain. LPV demonstrated activity similar to that observed against HIV-1 in two HIV-2 strains (HIV-2(MS) and HIV-2(CBL-23)) tested. On the other hand, approximately 10-fold-reduced susceptibility was observed with the third HIV-2 strain, HIV-2(CDC310319). Passage of HIV-2(MS) with increasing concentrations of LPV selected mutations V47A and D17N in the HIV-2 protease gene. The introduction of both 17N and 47A either individually or together into HIV-2(ROD) molecular infectious clones showed that the single V47A substitution in HIV-2 resulted in a substantial reduction in susceptibility to LPV. In contrast, this mutant retained wild-type susceptibility to other PIs and appeared to be hypersusceptible to atazanavir and saquinavir.
|
Antiviral activity against HIV1 LAI infected in human CEM-SS cells assessed as reverse transcriptase activity after 5 days by MTT assay
|
Human immunodeficiency virus 1
|
2.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and in vitro biological evaluation of valine-containing prodrugs derived from clinically used HIV-protease inhibitors.
Year : 2008
Volume : 43
Issue : 7
First Page : 1506
Last Page : 1518
Authors : Roche D, Greiner J, Aubertin AM, Vierling P.
Abstract : In an approach to improve the pharmacological properties and pharmacokinetic profiles of the current protease inhibitors (PIs) used in clinics, and consequently, their therapeutic potential, we performed the synthesis of PI-spacer-valine prodrugs (PI=saquinavir, nelfinavir and indinavir; spacer=-C(O)(CH(2))(5)NH-), and evaluated their in vitro stability with respect to hydrolysis, anti-HIV activity, cytotoxicity, and permeation through a monolayer of Caco-2 cells (used as a model of the intestinal barrier), as compared with their parent PI and first generation of valine-PIs (wherein valine was directly connected through its carboxyl to the PIs). The PI-spacer-valine conjugates were prepared in two steps, in good yields, by condensing an acid derivative of the appropriate protected valine-spacer moiety with the PI, followed by deprotection of the valine protecting group. With respect to hydrolysis, we found that the PI-spacer-valine prodrugs were chemically more stable than the first generation of PI-Val prodrugs. Their stabilities correlated with the low to very low in vitro anti-HIV activity measured for those prodrugs wherein the coupling of valine-spacer residue to the PIs was performed onto the peptidomimetic PI's hydroxyl. Prodrugs wherein the coupling of the valine-spacer residue was performed onto the non-peptidomimetic PI hydroxyl displayed a higher antiviral activity, indicating that these prodrugs are also to some extent anti-HIV drugs by themselves. While the direct conjugation of L-valine to the PIs constituted a most appealing alternative, which improved their absorptive diffusion across Caco-2 cell monolayers and reduced their recognition by efflux carriers, its conjugation to the PIs through the -C(O)(CH(2))(5)NH- spacer was found to inhibit their absorptive and secretory transepithelial transport. This was attributable to a drastic reduction of their passive permeation and/or active transport, indicating that the PI-spacer-valine conjugates are poor substrates of the aminoacid carrier system located at the brush border side of the Caco-2 cell monolayer.
|
Inhibition of HIV1 protease
|
Human immunodeficiency virus 1
|
0.306
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro antiviral activity and cross-resistance profile of PL-100, a novel protease inhibitor of human immunodeficiency virus type 1.
Year : 2007
Volume : 51
Issue : 11
First Page : 4036
Last Page : 4043
Authors : Dandache S, Sévigny G, Yelle J, Stranix BR, Parkin N, Schapiro JM, Wainberg MA, Wu JJ.
Abstract : Despite the success of highly active antiretroviral therapy, the current emergence and spread of drug-resistant variants of human immunodeficiency virus (HIV) stress the need for new inhibitors with distinct properties. We designed, produced, and screened a library of compounds based on an original l-lysine scaffold for their potentials as HIV type 1 (HIV-1) protease inhibitors (PI). One candidate compound, PL-100, emerged as a specific and noncytotoxic PI that exhibited potent inhibition of HIV-1 protease and viral replication in vitro (K(i), approximately 36 pM, and 50% effective concentration [EC(50)], approximately 16 nM, respectively). To confirm that PL-100 possessed a favorable resistance profile, we performed a cross-resistance study using a panel of 63 viral strains from PI-experienced patients selected for the presence of primary PI mutations known to confer resistance to multiple PIs now in clinical use. The results showed that PL-100 retained excellent antiviral activity against almost all of these PI-resistant viruses and that its performance in this regard was superior to those of atazanavir, amprenavir, indinavir, lopinavir, nelfinavir, and saquinavir. In almost every case, the increase in the EC(50) for PL-100 observed with viruses containing multiple mutations in protease was far less than that obtained with the other drugs tested. These data underscore the potential for PL-100 to be used in the treatment of drug-resistant HIV disease and argue for its further development.
|
Antiviral activity against wild type HIV1 NL4-3 infected in MT4 cells after 6 days by MTT assay
|
Human immunodeficiency virus 1
|
29.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro antiviral activity and cross-resistance profile of PL-100, a novel protease inhibitor of human immunodeficiency virus type 1.
Year : 2007
Volume : 51
Issue : 11
First Page : 4036
Last Page : 4043
Authors : Dandache S, Sévigny G, Yelle J, Stranix BR, Parkin N, Schapiro JM, Wainberg MA, Wu JJ.
Abstract : Despite the success of highly active antiretroviral therapy, the current emergence and spread of drug-resistant variants of human immunodeficiency virus (HIV) stress the need for new inhibitors with distinct properties. We designed, produced, and screened a library of compounds based on an original l-lysine scaffold for their potentials as HIV type 1 (HIV-1) protease inhibitors (PI). One candidate compound, PL-100, emerged as a specific and noncytotoxic PI that exhibited potent inhibition of HIV-1 protease and viral replication in vitro (K(i), approximately 36 pM, and 50% effective concentration [EC(50)], approximately 16 nM, respectively). To confirm that PL-100 possessed a favorable resistance profile, we performed a cross-resistance study using a panel of 63 viral strains from PI-experienced patients selected for the presence of primary PI mutations known to confer resistance to multiple PIs now in clinical use. The results showed that PL-100 retained excellent antiviral activity against almost all of these PI-resistant viruses and that its performance in this regard was superior to those of atazanavir, amprenavir, indinavir, lopinavir, nelfinavir, and saquinavir. In almost every case, the increase in the EC(50) for PL-100 observed with viruses containing multiple mutations in protease was far less than that obtained with the other drugs tested. These data underscore the potential for PL-100 to be used in the treatment of drug-resistant HIV disease and argue for its further development.
|
Antiviral activity against wild type HIV1 NL4-3 in HEK293 cells after 48 hrs by replication-deffective luciferase reporter gene-based phenotypic assay
|
Human immunodeficiency virus 1
|
5.8
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro antiviral activity and cross-resistance profile of PL-100, a novel protease inhibitor of human immunodeficiency virus type 1.
Year : 2007
Volume : 51
Issue : 11
First Page : 4036
Last Page : 4043
Authors : Dandache S, Sévigny G, Yelle J, Stranix BR, Parkin N, Schapiro JM, Wainberg MA, Wu JJ.
Abstract : Despite the success of highly active antiretroviral therapy, the current emergence and spread of drug-resistant variants of human immunodeficiency virus (HIV) stress the need for new inhibitors with distinct properties. We designed, produced, and screened a library of compounds based on an original l-lysine scaffold for their potentials as HIV type 1 (HIV-1) protease inhibitors (PI). One candidate compound, PL-100, emerged as a specific and noncytotoxic PI that exhibited potent inhibition of HIV-1 protease and viral replication in vitro (K(i), approximately 36 pM, and 50% effective concentration [EC(50)], approximately 16 nM, respectively). To confirm that PL-100 possessed a favorable resistance profile, we performed a cross-resistance study using a panel of 63 viral strains from PI-experienced patients selected for the presence of primary PI mutations known to confer resistance to multiple PIs now in clinical use. The results showed that PL-100 retained excellent antiviral activity against almost all of these PI-resistant viruses and that its performance in this regard was superior to those of atazanavir, amprenavir, indinavir, lopinavir, nelfinavir, and saquinavir. In almost every case, the increase in the EC(50) for PL-100 observed with viruses containing multiple mutations in protease was far less than that obtained with the other drugs tested. These data underscore the potential for PL-100 to be used in the treatment of drug-resistant HIV disease and argue for its further development.
|
Antiviral activity against HIV1
|
Human immunodeficiency virus 1
|
27.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Unified QSAR approach to antimicrobials. 4. Multi-target QSAR modeling and comparative multi-distance study of the giant components of antiviral drug-drug complex networks.
Year : 2009
Volume : 17
Issue : 2
First Page : 569
Last Page : 575
Authors : Prado-Prado FJ, Martinez de la Vega O, Uriarte E, Ubeira FM, Chou KC, González-Díaz H.
Abstract : One limitation of almost all antiviral Quantitative Structure-Activity Relationships (QSAR) models is that they predict the biological activity of drugs against only one species of virus. Consequently, the development of multi-tasking QSAR models (mt-QSAR) to predict drugs activity against different species of virus is of the major vitally important. These mt-QSARs offer also a good opportunity to construct drug-drug Complex Networks (CNs) that can be used to explore large and complex drug-viral species databases. It is known that in very large CNs we can use the Giant Component (GC) as a representative sub-set of nodes (drugs) and but the drug-drug similarity function selected may strongly determines the final network obtained. In the three previous works of the present series we reported mt-QSAR models to predict the antimicrobial activity against different fungi [Gonzalez-Diaz, H.; Prado-Prado, F. J.; Santana, L.; Uriarte, E. Bioorg.Med.Chem.2006, 14, 5973], bacteria [Prado-Prado, F. J.; Gonzalez-Diaz, H.; Santana, L.; Uriarte E. Bioorg.Med.Chem.2007, 15, 897] or parasite species [Prado-Prado, F.J.; González-Díaz, H.; Martinez de la Vega, O.; Ubeira, F.M.; Chou K.C. Bioorg.Med.Chem.2008, 16, 5871]. However, including these works, we do not found any report of mt-QSAR models for antivirals drug, or a comparative study of the different GC extracted from drug-drug CNs based on different similarity functions. In this work, we used Linear Discriminant Analysis (LDA) to fit a mt-QSAR model that classify 600 drugs as active or non-active against the 41 different tested species of virus. The model correctly classifies 143 of 169 active compounds (specificity=84.62%) and 119 of 139 non-active compounds (sensitivity=85.61%) and presents overall training accuracy of 85.1% (262 of 308 cases). Validation of the model was carried out by means of external predicting series, classifying the model 466 of 514, 90.7% of compounds. In order to illustrate the performance of the model in practice, we develop a virtual screening recognizing the model as active 92.7%, 102 of 110 antivirus compounds. These compounds were never use in training or predicting series. Next, we obtained and compared the topology of the CNs and their respective GCs based on Euclidean, Manhattan, Chebychey, Pearson and other similarity measures. The GC of the Manhattan network showed the more interesting features for drug-drug similarity search. We also give the procedure for the construction of Back-Projection Maps for the contribution of each drug sub-structure to the antiviral activity against different species.
|
Antiviral activity against HIV1 BaL in human PBMC assessed as blockade of reverse transcriptase activity
|
Human immunodeficiency virus 1
|
36.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro antiviral activity of the novel, tyrosyl-based human immunodeficiency virus (HIV) type 1 protease inhibitor brecanavir (GW640385) in combination with other antiretrovirals and against a panel of protease inhibitor-resistant HIV.
Year : 2007
Volume : 51
Issue : 9
First Page : 3147
Last Page : 3154
Authors : Hazen R, Harvey R, Ferris R, Craig C, Yates P, Griffin P, Miller J, Kaldor I, Ray J, Samano V, Furfine E, Spaltenstein A, Hale M, Tung R, St Clair M, Hanlon M, Boone L.
Abstract : Brecanavir, a novel tyrosyl-based arylsulfonamide, high-affinity, human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI), has been evaluated for anti-HIV activity in several in vitro assays. Preclinical assessment of brecanavir indicated that this compound potently inhibited HIV-1 in cell culture assays with 50% effective concentrations (EC(50)s) of 0.2 to 0.53 nM and was equally active against HIV strains utilizing either the CXCR4 or CCR5 coreceptor, as was found with other PIs. The presence of up to 40% human serum decreased the anti-HIV-1 activity of brecanavir by 5.2-fold, but under these conditions the compound retained single-digit nanomolar EC(50)s. When brecanavir was tested in combination with nucleoside reverse transcriptase inhibitors, the antiviral activity of brecanavir was synergistic with the effects of stavudine and additive to the effects of zidovudine, tenofovir, dideoxycytidine, didanosine, adefovir, abacavir, lamivudine, and emtricitabine. Brecanavir was synergistic with the nonnucleoside reverse transcriptase inhibitor nevirapine or delavirdine and was additive to the effects of efavirenz. In combination with other PIs, brecanavir was additive to the activities of indinavir, lopinavir, nelfinavir, ritonavir, amprenavir, saquinavir, and atazanavir. Clinical HIV isolates from PI-experienced patients were evaluated for sensitivity to brecanavir and other PIs in a recombinant virus assay. Brecanavir had a <5-fold increase in EC(50)s against 80% of patient isolates tested and had a greater mean in vitro potency than amprenavir, indinavir, lopinavir, atazanavir, tipranavir, and darunavir. Brecanavir is by a substantial margin the most potent and broadly active antiviral agent among the PIs tested in vitro.
|
Inhibition of HIV1 protease at 1 nM
|
Human immunodeficiency virus 1
|
29.0
%
|
|
Journal : J. Med. Chem.
Title : Combination of non-natural D-amino acid derivatives and allophenylnorstatine-dimethylthioproline scaffold in HIV protease inhibitors have high efficacy in mutant HIV.
Year : 2008
Volume : 51
Issue : 10
First Page : 2992
Last Page : 3004
Authors : Nakatani S, Hidaka K, Ami E, Nakahara K, Sato A, Nguyen JT, Hamada Y, Hori Y, Ohnishi N, Nagai A, Kimura T, Hayashi Y, Kiso Y.
Abstract : Several non-natural D-amino acid derivatives were introduced as P2/P3 residues in allophenylnorstatine-containing (Apns; (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid) HIV protease inhibitors. The synthetic analogues exhibited potent inhibitory activity against HIV-1 protease enzyme and HIV-1 replication in MT-4 cells. Structure-activity relationships revealed that D-cysteine or serine derivatives contributed to highly potent anti-HIV activities. Interestingly, anti-HIV activity of all the D-amino acid-introduced inhibitors was remarkably enhanced in their anti-HIV activities against a Nelfinavir-resistant clone, which has a D30N mutation in the protease, over that of the wild-type strain. HIV inhibitory activity of several analogues was moderately affected by an inclusion of alpha1-acid glycoprotein in the test medium.
|
Antiviral activity against HIV1 3B in human MT4 cells assessed as inhibition of viral-induced cytopathic effect by MTT method
|
Human immunodeficiency virus 1
|
16.0
nM
|
|
Journal : J. Med. Chem.
Title : Combination of non-natural D-amino acid derivatives and allophenylnorstatine-dimethylthioproline scaffold in HIV protease inhibitors have high efficacy in mutant HIV.
Year : 2008
Volume : 51
Issue : 10
First Page : 2992
Last Page : 3004
Authors : Nakatani S, Hidaka K, Ami E, Nakahara K, Sato A, Nguyen JT, Hamada Y, Hori Y, Ohnishi N, Nagai A, Kimura T, Hayashi Y, Kiso Y.
Abstract : Several non-natural D-amino acid derivatives were introduced as P2/P3 residues in allophenylnorstatine-containing (Apns; (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid) HIV protease inhibitors. The synthetic analogues exhibited potent inhibitory activity against HIV-1 protease enzyme and HIV-1 replication in MT-4 cells. Structure-activity relationships revealed that D-cysteine or serine derivatives contributed to highly potent anti-HIV activities. Interestingly, anti-HIV activity of all the D-amino acid-introduced inhibitors was remarkably enhanced in their anti-HIV activities against a Nelfinavir-resistant clone, which has a D30N mutation in the protease, over that of the wild-type strain. HIV inhibitory activity of several analogues was moderately affected by an inclusion of alpha1-acid glycoprotein in the test medium.
|
Antiviral activity against wild type HIV1 NL432
|
Human immunodeficiency virus 1
|
25.0
nM
|
|
Journal : J. Med. Chem.
Title : Combination of non-natural D-amino acid derivatives and allophenylnorstatine-dimethylthioproline scaffold in HIV protease inhibitors have high efficacy in mutant HIV.
Year : 2008
Volume : 51
Issue : 10
First Page : 2992
Last Page : 3004
Authors : Nakatani S, Hidaka K, Ami E, Nakahara K, Sato A, Nguyen JT, Hamada Y, Hori Y, Ohnishi N, Nagai A, Kimura T, Hayashi Y, Kiso Y.
Abstract : Several non-natural D-amino acid derivatives were introduced as P2/P3 residues in allophenylnorstatine-containing (Apns; (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid) HIV protease inhibitors. The synthetic analogues exhibited potent inhibitory activity against HIV-1 protease enzyme and HIV-1 replication in MT-4 cells. Structure-activity relationships revealed that D-cysteine or serine derivatives contributed to highly potent anti-HIV activities. Interestingly, anti-HIV activity of all the D-amino acid-introduced inhibitors was remarkably enhanced in their anti-HIV activities against a Nelfinavir-resistant clone, which has a D30N mutation in the protease, over that of the wild-type strain. HIV inhibitory activity of several analogues was moderately affected by an inclusion of alpha1-acid glycoprotein in the test medium.
|
Antiviral activity against nelfinavir-resistant HIV1 NL432
|
Human immunodeficiency virus 1
|
308.0
nM
|
|
Journal : J. Med. Chem.
Title : Combination of non-natural D-amino acid derivatives and allophenylnorstatine-dimethylthioproline scaffold in HIV protease inhibitors have high efficacy in mutant HIV.
Year : 2008
Volume : 51
Issue : 10
First Page : 2992
Last Page : 3004
Authors : Nakatani S, Hidaka K, Ami E, Nakahara K, Sato A, Nguyen JT, Hamada Y, Hori Y, Ohnishi N, Nagai A, Kimura T, Hayashi Y, Kiso Y.
Abstract : Several non-natural D-amino acid derivatives were introduced as P2/P3 residues in allophenylnorstatine-containing (Apns; (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid) HIV protease inhibitors. The synthetic analogues exhibited potent inhibitory activity against HIV-1 protease enzyme and HIV-1 replication in MT-4 cells. Structure-activity relationships revealed that D-cysteine or serine derivatives contributed to highly potent anti-HIV activities. Interestingly, anti-HIV activity of all the D-amino acid-introduced inhibitors was remarkably enhanced in their anti-HIV activities against a Nelfinavir-resistant clone, which has a D30N mutation in the protease, over that of the wild-type strain. HIV inhibitory activity of several analogues was moderately affected by an inclusion of alpha1-acid glycoprotein in the test medium.
|
Antiviral activity against ritonavir-resistant HIV1 NL432
|
Human immunodeficiency virus 1
|
28.0
nM
|
|
Journal : J. Med. Chem.
Title : Combination of non-natural D-amino acid derivatives and allophenylnorstatine-dimethylthioproline scaffold in HIV protease inhibitors have high efficacy in mutant HIV.
Year : 2008
Volume : 51
Issue : 10
First Page : 2992
Last Page : 3004
Authors : Nakatani S, Hidaka K, Ami E, Nakahara K, Sato A, Nguyen JT, Hamada Y, Hori Y, Ohnishi N, Nagai A, Kimura T, Hayashi Y, Kiso Y.
Abstract : Several non-natural D-amino acid derivatives were introduced as P2/P3 residues in allophenylnorstatine-containing (Apns; (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid) HIV protease inhibitors. The synthetic analogues exhibited potent inhibitory activity against HIV-1 protease enzyme and HIV-1 replication in MT-4 cells. Structure-activity relationships revealed that D-cysteine or serine derivatives contributed to highly potent anti-HIV activities. Interestingly, anti-HIV activity of all the D-amino acid-introduced inhibitors was remarkably enhanced in their anti-HIV activities against a Nelfinavir-resistant clone, which has a D30N mutation in the protease, over that of the wild-type strain. HIV inhibitory activity of several analogues was moderately affected by an inclusion of alpha1-acid glycoprotein in the test medium.
|
Antiviral activity against ritonavir and nelfinavir-resistant HIV1 NL432
|
Human immunodeficiency virus 1
|
67.0
nM
|
|
Journal : J. Med. Chem.
Title : Combination of non-natural D-amino acid derivatives and allophenylnorstatine-dimethylthioproline scaffold in HIV protease inhibitors have high efficacy in mutant HIV.
Year : 2008
Volume : 51
Issue : 10
First Page : 2992
Last Page : 3004
Authors : Nakatani S, Hidaka K, Ami E, Nakahara K, Sato A, Nguyen JT, Hamada Y, Hori Y, Ohnishi N, Nagai A, Kimura T, Hayashi Y, Kiso Y.
Abstract : Several non-natural D-amino acid derivatives were introduced as P2/P3 residues in allophenylnorstatine-containing (Apns; (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid) HIV protease inhibitors. The synthetic analogues exhibited potent inhibitory activity against HIV-1 protease enzyme and HIV-1 replication in MT-4 cells. Structure-activity relationships revealed that D-cysteine or serine derivatives contributed to highly potent anti-HIV activities. Interestingly, anti-HIV activity of all the D-amino acid-introduced inhibitors was remarkably enhanced in their anti-HIV activities against a Nelfinavir-resistant clone, which has a D30N mutation in the protease, over that of the wild-type strain. HIV inhibitory activity of several analogues was moderately affected by an inclusion of alpha1-acid glycoprotein in the test medium.
|
Antiviral activity against HIV1 3B in presence of 10% fetal calf serum
|
Human immunodeficiency virus 1
|
21.0
nM
|
|
Journal : J. Med. Chem.
Title : Combination of non-natural D-amino acid derivatives and allophenylnorstatine-dimethylthioproline scaffold in HIV protease inhibitors have high efficacy in mutant HIV.
Year : 2008
Volume : 51
Issue : 10
First Page : 2992
Last Page : 3004
Authors : Nakatani S, Hidaka K, Ami E, Nakahara K, Sato A, Nguyen JT, Hamada Y, Hori Y, Ohnishi N, Nagai A, Kimura T, Hayashi Y, Kiso Y.
Abstract : Several non-natural D-amino acid derivatives were introduced as P2/P3 residues in allophenylnorstatine-containing (Apns; (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid) HIV protease inhibitors. The synthetic analogues exhibited potent inhibitory activity against HIV-1 protease enzyme and HIV-1 replication in MT-4 cells. Structure-activity relationships revealed that D-cysteine or serine derivatives contributed to highly potent anti-HIV activities. Interestingly, anti-HIV activity of all the D-amino acid-introduced inhibitors was remarkably enhanced in their anti-HIV activities against a Nelfinavir-resistant clone, which has a D30N mutation in the protease, over that of the wild-type strain. HIV inhibitory activity of several analogues was moderately affected by an inclusion of alpha1-acid glycoprotein in the test medium.
|
Antiviral activity against HIV1 3B in presence of 10% fetal calf serum and alpha1 acid glycoprotein
|
Human immunodeficiency virus 1
|
606.0
nM
|
|
Journal : J. Med. Chem.
Title : Combination of non-natural D-amino acid derivatives and allophenylnorstatine-dimethylthioproline scaffold in HIV protease inhibitors have high efficacy in mutant HIV.
Year : 2008
Volume : 51
Issue : 10
First Page : 2992
Last Page : 3004
Authors : Nakatani S, Hidaka K, Ami E, Nakahara K, Sato A, Nguyen JT, Hamada Y, Hori Y, Ohnishi N, Nagai A, Kimura T, Hayashi Y, Kiso Y.
Abstract : Several non-natural D-amino acid derivatives were introduced as P2/P3 residues in allophenylnorstatine-containing (Apns; (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid) HIV protease inhibitors. The synthetic analogues exhibited potent inhibitory activity against HIV-1 protease enzyme and HIV-1 replication in MT-4 cells. Structure-activity relationships revealed that D-cysteine or serine derivatives contributed to highly potent anti-HIV activities. Interestingly, anti-HIV activity of all the D-amino acid-introduced inhibitors was remarkably enhanced in their anti-HIV activities against a Nelfinavir-resistant clone, which has a D30N mutation in the protease, over that of the wild-type strain. HIV inhibitory activity of several analogues was moderately affected by an inclusion of alpha1-acid glycoprotein in the test medium.
|
Antiviral activity against HIV1 bearing HIV1 NL4-3 envelope infected in human MT2 cells assessed as inhibition of HIV-envelope packed virions at 0.12 uM after 72 hrs by virus production assay relative to control
|
Human immunodeficiency virus 1
|
88.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Identification and characterization of UK-201844, a novel inhibitor that interferes with human immunodeficiency virus type 1 gp160 processing.
Year : 2007
Volume : 51
Issue : 10
First Page : 3554
Last Page : 3561
Authors : Blair WS, Cao J, Jackson L, Jimenez J, Peng Q, Wu H, Isaacson J, Butler SL, Chu A, Graham J, Malfait AM, Tortorella M, Patick AK.
Abstract : More than 10(6) compounds were evaluated in a human immunodeficiency virus type 1 (HIV-1) high-throughput antiviral screen, resulting in the identification of a novel HIV-1 inhibitor (UK-201844). UK-201844 exhibited antiviral activity against HIV-1 NL4-3 in MT-2 and PM1 cells, with 50% effective concentrations of 1.3 and 2.7 microM, respectively, but did not exhibit measurable antiviral activity against the closely related HIV-1 IIIB laboratory strain. UK-201844 specifically inhibited the production of infectious virions packaged with an HIV-1 envelope (Env), but not HIV virions packaged with a heterologous Env (i.e., the vesicular stomatitis virus glycoprotein), suggesting that the compound targets HIV-1 Env late in infection. Subsequent antiviral assays using HIV-1 NL4-3/IIIB chimeric viruses showed that HIV-1 Env sequences were critical determinants of UK-201844 susceptibility. Consistent with this, in vitro resistant-virus studies revealed that amino acid substitutions in HIV-1 Env are sufficient to confer resistance to UK-201844. Western analysis of HIV Env proteins expressed in transfected cells or in isolated virions showed that UK-201844 inhibited HIV-1 gp160 processing, resulting in the production of virions with nonfunctional Env glycoproteins. Our results demonstrate that UK-201844 represents the prototype for a unique HIV-1 inhibitor class that directly or indirectly interferes with HIV-1 gp160 processing.
|
Antiviral activity against HIV1 bearing VSV envelope infected in human MT2 cells assessed as inhibition of VSV-envelope packed virions at 0.12 uM after 72 hrs by virus production assay relative to control
|
Human immunodeficiency virus 1
|
97.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Identification and characterization of UK-201844, a novel inhibitor that interferes with human immunodeficiency virus type 1 gp160 processing.
Year : 2007
Volume : 51
Issue : 10
First Page : 3554
Last Page : 3561
Authors : Blair WS, Cao J, Jackson L, Jimenez J, Peng Q, Wu H, Isaacson J, Butler SL, Chu A, Graham J, Malfait AM, Tortorella M, Patick AK.
Abstract : More than 10(6) compounds were evaluated in a human immunodeficiency virus type 1 (HIV-1) high-throughput antiviral screen, resulting in the identification of a novel HIV-1 inhibitor (UK-201844). UK-201844 exhibited antiviral activity against HIV-1 NL4-3 in MT-2 and PM1 cells, with 50% effective concentrations of 1.3 and 2.7 microM, respectively, but did not exhibit measurable antiviral activity against the closely related HIV-1 IIIB laboratory strain. UK-201844 specifically inhibited the production of infectious virions packaged with an HIV-1 envelope (Env), but not HIV virions packaged with a heterologous Env (i.e., the vesicular stomatitis virus glycoprotein), suggesting that the compound targets HIV-1 Env late in infection. Subsequent antiviral assays using HIV-1 NL4-3/IIIB chimeric viruses showed that HIV-1 Env sequences were critical determinants of UK-201844 susceptibility. Consistent with this, in vitro resistant-virus studies revealed that amino acid substitutions in HIV-1 Env are sufficient to confer resistance to UK-201844. Western analysis of HIV Env proteins expressed in transfected cells or in isolated virions showed that UK-201844 inhibited HIV-1 gp160 processing, resulting in the production of virions with nonfunctional Env glycoproteins. Our results demonstrate that UK-201844 represents the prototype for a unique HIV-1 inhibitor class that directly or indirectly interferes with HIV-1 gp160 processing.
|
Inhibition of human MDR1-dependent accumulation of calcein-AM expressed in MDCK2 cells at 20 uM
|
Homo sapiens
|
50.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Effects of human immunodeficiency virus protease inhibitors on the intestinal absorption of tenofovir disoproxil fumarate in vitro.
Year : 2007
Volume : 51
Issue : 10
First Page : 3498
Last Page : 3504
Authors : Tong L, Phan TK, Robinson KL, Babusis D, Strab R, Bhoopathy S, Hidalgo IJ, Rhodes GR, Ray AS.
Abstract : Human immunodeficiency virus protease inhibitors (PIs) modestly affect the plasma pharmacokinetics of tenofovir (TFV; -15% to +37% change in exposure) following coadministration with the oral prodrug TFV disoproxil fumarate (TDF) by a previously undefined mechanism. TDF permeation was found to be reduced by the combined action of ester cleavage and efflux transport in vitro. Saturable TDF efflux observed in Caco-2 cells suggests that at pharmacologically relevant intestinal concentrations, transport has only a limited effect on TDF absorption, thus minimizing the magnitude of potential intestinal drug interactions. Most tested PIs increased apical-to-basolateral TDF permeation and decreased secretory transport in MDCKII cells overexpressing P-glycoprotein (Pgp; MDCKII-MDR1 cells) and Caco-2 cells. PIs were found to cause a multifactorial effect on the barriers to TDF absorption. All PIs showed similar levels of inhibition of esterase-dependent degradation of TDF in an intestinal subcellular fraction, except for amprenavir, which was found to be a weaker inhibitor. All PIs caused a dose-dependent increase in the accumulation of a model Pgp substrate in MDCKII-MDR1 cells. Pgp inhibition constants ranged from 10.3 microM (lopinavir) to >100 microM (amprenavir, indinavir, and darunavir). Analogous to hepatic cytochrome P450-mediated drug interactions, we propose that the relative differences in perturbations in TFV plasma levels when TDF is coadministered with PIs are based in part on the net effect of inhibition and induction of intestinal Pgp by PIs. Combined with prior studies, these findings indicate that intestinal absorption is the mechanism for changes in TFV plasma levels when TDF is coadministered with PIs.
|
Antiviral activity against HIV1 Ba-L(R5) infected in human PBMC by p24 antigen capture assay
|
Human immunodeficiency virus 1
|
12.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Spirodiketopiperazine-based CCR5 antagonists: Improvement of their pharmacokinetic profiles.
Year : 2010
Volume : 20
Issue : 2
First Page : 763
Last Page : 766
Authors : Nishizawa R, Nishiyama T, Hisaichi K, Hirai K, Habashita H, Takaoka Y, Tada H, Sagawa K, Shibayama S, Maeda K, Mitsuya H, Nakai H, Fukushima D, Toda M.
Abstract : Spirodiketopiperazine-based CCR5 antagonists, showing improved pharmacokinetic profiles without reduction in antagonist activity, were designed and synthesized. We also demonstrate the anti-HIV activity of a representative compound 12, as measured in a p24 assay.
|
Inhibition of recombinant wild type HIV1 protease assessed as hydrolysis of fluorogenic substrate
|
Human immunodeficiency virus 1
|
1.9
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of new thienyl ring containing HIV-1 protease inhibitors: promising preliminary pharmacological evaluation against recombinant HIV-1 proteases.
Year : 2010
Volume : 53
Issue : 4
First Page : 1451
Last Page : 1457
Authors : Bonini C, Chiummiento L, De Bonis M, Di Blasio N, Funicello M, Lupattelli P, Pandolfo R, Tramutola F, Berti F.
Abstract : A series of new thienyl ring containing analogues of nelfinavir and saquinavir with different substitution patterns were synthesized from suitable enantiopure diols. Their inhibitory activity against wild type recombinant HIV-1 protease was evaluated. In general thienyl groups spaced from the core by a methylene group gave products showing IC(50) in the nanomolar range, irrespective of the type and the substitution pattern of the heterocycle. The range of activity of the two most active compounds is substantially maintained or even increased against two commonly selected mutants, under drug pressure, such as V32I and V82A.
|
Antiviral activity against HIV1 BAL by p24 assay
|
Human immunodeficiency virus 1
|
12.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of orally available spirodiketopiperazine-based CCR5 antagonists.
Year : 2010
Volume : 18
Issue : 14
First Page : 5208
Last Page : 5223
Authors : Nishizawa R, Nishiyama T, Hisaichi K, Hirai K, Habashita H, Takaoka Y, Tada H, Sagawa K, Shibayama S, Maeda K, Mitsuya H, Nakai H, Fukushima D, Toda M.
Abstract : Using the previously reported novel spirodiketopiperazine scaffold, the design and synthesis of orally available CCR5 antagonists was undertaken. Compounds possessing a carboxylic acid function in the appropriate position showed improved oral exposure (AUC) relative to the initial chemical leads without reduction in the antagonist activity. The optimized compound 40 was found to show potent anti-HIV activity. Full details of structure-activity relationship (SAR) study are presented.
|
Antiviral activity against HIV 2 subtype A clinical isolate expressing 14H-17D-43T-68N/D protease gene sequence from HIV2 infected patient plasma and PBMC obtained before compound treatment measured after 13 months
|
Human immunodeficiency virus 2
|
30.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro phenotypic susceptibility of human immunodeficiency virus type 2 clinical isolates to protease inhibitors.
Year : 2008
Volume : 52
Issue : 4
First Page : 1545
Last Page : 1548
Authors : Desbois D, Roquebert B, Peytavin G, Damond F, Collin G, Bénard A, Campa P, Matheron S, Chêne G, Brun-Vézinet F, Descamps D, French ANRS HIV-2 Cohort (ANRS CO 05 VIH-2).
Abstract : We determine phenotypic susceptibility of human immunodeficiency virus type 2 (HIV-2) isolates to amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, saquinavir, and tipranavir. Saquinavir, lopinavir, and darunavir are potent against wild-type HIV-2 isolates and should be preferred as first-line options for HIV-2-infected patients. Other protease inhibitors are less active against HIV-2 than against HIV-1.
|
Antiviral activity against HIV 2 subtype A clinical isolate expressing 14H-60K/N-65E protease gene sequence from HIV2 infected patient plasma and PBMC obtained before compound treatment measured after 13 months
|
Human immunodeficiency virus 2
|
60.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro phenotypic susceptibility of human immunodeficiency virus type 2 clinical isolates to protease inhibitors.
Year : 2008
Volume : 52
Issue : 4
First Page : 1545
Last Page : 1548
Authors : Desbois D, Roquebert B, Peytavin G, Damond F, Collin G, Bénard A, Campa P, Matheron S, Chêne G, Brun-Vézinet F, Descamps D, French ANRS HIV-2 Cohort (ANRS CO 05 VIH-2).
Abstract : We determine phenotypic susceptibility of human immunodeficiency virus type 2 (HIV-2) isolates to amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, saquinavir, and tipranavir. Saquinavir, lopinavir, and darunavir are potent against wild-type HIV-2 isolates and should be preferred as first-line options for HIV-2-infected patients. Other protease inhibitors are less active against HIV-2 than against HIV-1.
|
Antiviral activity against HIV 2 subtype A clinical isolate expressing 10I-17D-40D-43I-46V-66V/A-70R/K protease gene sequence from HIV2 infected patient plasma and PBMC obtained before compound treatment measured after 13 months
|
Human immunodeficiency virus 2
|
50.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro phenotypic susceptibility of human immunodeficiency virus type 2 clinical isolates to protease inhibitors.
Year : 2008
Volume : 52
Issue : 4
First Page : 1545
Last Page : 1548
Authors : Desbois D, Roquebert B, Peytavin G, Damond F, Collin G, Bénard A, Campa P, Matheron S, Chêne G, Brun-Vézinet F, Descamps D, French ANRS HIV-2 Cohort (ANRS CO 05 VIH-2).
Abstract : We determine phenotypic susceptibility of human immunodeficiency virus type 2 (HIV-2) isolates to amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, saquinavir, and tipranavir. Saquinavir, lopinavir, and darunavir are potent against wild-type HIV-2 isolates and should be preferred as first-line options for HIV-2-infected patients. Other protease inhibitors are less active against HIV-2 than against HIV-1.
|
Antiviral activity against HIV 2 subtype A clinical isolate expressing 14H-40D-70K-72R/K-91T/S protease gene sequence from HIV2 infected patient plasma and PBMC obtained before compound treatment measured after 13 months
|
Human immunodeficiency virus 2
|
200.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro phenotypic susceptibility of human immunodeficiency virus type 2 clinical isolates to protease inhibitors.
Year : 2008
Volume : 52
Issue : 4
First Page : 1545
Last Page : 1548
Authors : Desbois D, Roquebert B, Peytavin G, Damond F, Collin G, Bénard A, Campa P, Matheron S, Chêne G, Brun-Vézinet F, Descamps D, French ANRS HIV-2 Cohort (ANRS CO 05 VIH-2).
Abstract : We determine phenotypic susceptibility of human immunodeficiency virus type 2 (HIV-2) isolates to amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, saquinavir, and tipranavir. Saquinavir, lopinavir, and darunavir are potent against wild-type HIV-2 isolates and should be preferred as first-line options for HIV-2-infected patients. Other protease inhibitors are less active against HIV-2 than against HIV-1.
|
Antiviral activity against HIV 2 subtype B clinical isolate expressing 14Y-61N-99L protease gene sequence from HIV2 infected patient plasma and PBMC obtained before compound treatment measured after 13 months
|
Human immunodeficiency virus 2
|
200.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro phenotypic susceptibility of human immunodeficiency virus type 2 clinical isolates to protease inhibitors.
Year : 2008
Volume : 52
Issue : 4
First Page : 1545
Last Page : 1548
Authors : Desbois D, Roquebert B, Peytavin G, Damond F, Collin G, Bénard A, Campa P, Matheron S, Chêne G, Brun-Vézinet F, Descamps D, French ANRS HIV-2 Cohort (ANRS CO 05 VIH-2).
Abstract : We determine phenotypic susceptibility of human immunodeficiency virus type 2 (HIV-2) isolates to amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, saquinavir, and tipranavir. Saquinavir, lopinavir, and darunavir are potent against wild-type HIV-2 isolates and should be preferred as first-line options for HIV-2-infected patients. Other protease inhibitors are less active against HIV-2 than against HIV-1.
|
Antiviral activity against HIV 2 subtype B clinical isolate expressing 12T-14Y-19P-40N-41D-61N-62I-96S-99L protease gene sequence from HIV2 infected patient plasma and PBMC obtained before compound treatment measured after 13 months
|
Human immunodeficiency virus 2
|
60.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro phenotypic susceptibility of human immunodeficiency virus type 2 clinical isolates to protease inhibitors.
Year : 2008
Volume : 52
Issue : 4
First Page : 1545
Last Page : 1548
Authors : Desbois D, Roquebert B, Peytavin G, Damond F, Collin G, Bénard A, Campa P, Matheron S, Chêne G, Brun-Vézinet F, Descamps D, French ANRS HIV-2 Cohort (ANRS CO 05 VIH-2).
Abstract : We determine phenotypic susceptibility of human immunodeficiency virus type 2 (HIV-2) isolates to amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, saquinavir, and tipranavir. Saquinavir, lopinavir, and darunavir are potent against wild-type HIV-2 isolates and should be preferred as first-line options for HIV-2-infected patients. Other protease inhibitors are less active against HIV-2 than against HIV-1.
|
Antiviral activity against HIV 2 subtype B clinical isolate expressing 12Q-14R-17G/D-19P-61N-62I-92A protease gene sequence from HIV2 infected patient plasma and PBMC obtained before compound treatment measured after 13 months
|
Human immunodeficiency virus 2
|
40.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro phenotypic susceptibility of human immunodeficiency virus type 2 clinical isolates to protease inhibitors.
Year : 2008
Volume : 52
Issue : 4
First Page : 1545
Last Page : 1548
Authors : Desbois D, Roquebert B, Peytavin G, Damond F, Collin G, Bénard A, Campa P, Matheron S, Chêne G, Brun-Vézinet F, Descamps D, French ANRS HIV-2 Cohort (ANRS CO 05 VIH-2).
Abstract : We determine phenotypic susceptibility of human immunodeficiency virus type 2 (HIV-2) isolates to amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, saquinavir, and tipranavir. Saquinavir, lopinavir, and darunavir are potent against wild-type HIV-2 isolates and should be preferred as first-line options for HIV-2-infected patients. Other protease inhibitors are less active against HIV-2 than against HIV-1.
|
Antiviral activity against HIV 2 subtype B clinical isolate expressing 41D protease gene sequence from HIV2 infected patient plasma and PBMC obtained before compound treatment measured after 13 months
|
Human immunodeficiency virus 2
|
200.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro phenotypic susceptibility of human immunodeficiency virus type 2 clinical isolates to protease inhibitors.
Year : 2008
Volume : 52
Issue : 4
First Page : 1545
Last Page : 1548
Authors : Desbois D, Roquebert B, Peytavin G, Damond F, Collin G, Bénard A, Campa P, Matheron S, Chêne G, Brun-Vézinet F, Descamps D, French ANRS HIV-2 Cohort (ANRS CO 05 VIH-2).
Abstract : We determine phenotypic susceptibility of human immunodeficiency virus type 2 (HIV-2) isolates to amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, saquinavir, and tipranavir. Saquinavir, lopinavir, and darunavir are potent against wild-type HIV-2 isolates and should be preferred as first-line options for HIV-2-infected patients. Other protease inhibitors are less active against HIV-2 than against HIV-1.
|
Antiviral activity against HIV1 3B infected in MOLT-4/3B cells assessed as inhibition of mature virus release measured after 4 days of infection by RT assay
|
Human immunodeficiency virus 1
|
29.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Entecavir exhibits inhibitory activity against human immunodeficiency virus under conditions of reduced viral challenge.
Year : 2008
Volume : 52
Issue : 5
First Page : 1759
Last Page : 1767
Authors : Lin PF, Nowicka-Sans B, Terry B, Zhang S, Wang C, Fan L, Dicker I, Gali V, Higley H, Parkin N, Tenney D, Krystal M, Colonno R.
Abstract : Entecavir (ETV) was developed for the treatment of chronic hepatitis B virus (HBV) infection and is globally approved for that indication. Initial preclinical studies indicated that ETV had no significant activity against human immunodeficiency virus type 1 (HIV-1) in cultured cell lines at physiologically relevant ETV concentrations, using traditional anti-HIV assays. In response to recent clinical observations of anti-HIV activity of ETV in HIV/HBV-coinfected patients not receiving highly active antiretroviral therapy (HAART), additional investigative studies were conducted to expand upon earlier results. An extended panel of HIV-1 laboratory and clinical strains and cell types was tested against ETV, along with a comparison of assay methodologies and resistance profiling. These latest studies confirmed that ETV has only weak activity against HIV, using established assay systems. However, a >100-fold enhancement of antiviral activity (equivalent to the antiviral activity of lamivudine) could be obtained when assay conditions were modified to reduce the initial viral challenge. Also, the selection of a M184I virus variant during the passage of HIV-1 at high concentrations of ETV confirmed that ETV can exert inhibitory pressure on the virus. These findings may have a significant impact on how future assays are performed with compounds to be used in patients infected with HIV. These results support the recommendation that ETV therapy should be administered in concert with HAART for HIV/HBV-coinfected patients.
|
Antiviral activity against Human immunodeficiency virus type 2 (ISOLATE ROD) after 13 months
|
Human immunodeficiency virus type 2 (ISOLATE ROD)
|
50.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro phenotypic susceptibility of human immunodeficiency virus type 2 clinical isolates to protease inhibitors.
Year : 2008
Volume : 52
Issue : 4
First Page : 1545
Last Page : 1548
Authors : Desbois D, Roquebert B, Peytavin G, Damond F, Collin G, Bénard A, Campa P, Matheron S, Chêne G, Brun-Vézinet F, Descamps D, French ANRS HIV-2 Cohort (ANRS CO 05 VIH-2).
Abstract : We determine phenotypic susceptibility of human immunodeficiency virus type 2 (HIV-2) isolates to amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, saquinavir, and tipranavir. Saquinavir, lopinavir, and darunavir are potent against wild-type HIV-2 isolates and should be preferred as first-line options for HIV-2-infected patients. Other protease inhibitors are less active against HIV-2 than against HIV-1.
|
Antiviral activity against Human immunodeficiency virus type 1 (BRU ISOLATE) after 13 months
|
Human immunodeficiency virus type 1 (BRU ISOLATE)
|
2.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro phenotypic susceptibility of human immunodeficiency virus type 2 clinical isolates to protease inhibitors.
Year : 2008
Volume : 52
Issue : 4
First Page : 1545
Last Page : 1548
Authors : Desbois D, Roquebert B, Peytavin G, Damond F, Collin G, Bénard A, Campa P, Matheron S, Chêne G, Brun-Vézinet F, Descamps D, French ANRS HIV-2 Cohort (ANRS CO 05 VIH-2).
Abstract : We determine phenotypic susceptibility of human immunodeficiency virus type 2 (HIV-2) isolates to amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, saquinavir, and tipranavir. Saquinavir, lopinavir, and darunavir are potent against wild-type HIV-2 isolates and should be preferred as first-line options for HIV-2-infected patients. Other protease inhibitors are less active against HIV-2 than against HIV-1.
|
Antiviral activity against HIV 2 subtype H expressing 10I-40P-41Y-60H-63N-70T-73G-89L-92E protease gene sequence from HIV2 infected patient plasma and PBMC obtained before compound treatment measured after 13 months
|
Human immunodeficiency virus 2
|
40.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro phenotypic susceptibility of human immunodeficiency virus type 2 clinical isolates to protease inhibitors.
Year : 2008
Volume : 52
Issue : 4
First Page : 1545
Last Page : 1548
Authors : Desbois D, Roquebert B, Peytavin G, Damond F, Collin G, Bénard A, Campa P, Matheron S, Chêne G, Brun-Vézinet F, Descamps D, French ANRS HIV-2 Cohort (ANRS CO 05 VIH-2).
Abstract : We determine phenotypic susceptibility of human immunodeficiency virus type 2 (HIV-2) isolates to amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, saquinavir, and tipranavir. Saquinavir, lopinavir, and darunavir are potent against wild-type HIV-2 isolates and should be preferred as first-line options for HIV-2-infected patients. Other protease inhibitors are less active against HIV-2 than against HIV-1.
|
Antiviral activity against wild type HIV1 subtype B infected in human cord blood mononuclear cells assessed as inhibition of viral replication after 48 hrs by luciferase reporter gene assay
|
Human immunodeficiency virus 1
|
9.8
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : HIV-1 protease codon 36 polymorphisms and differential development of resistance to nelfinavir, lopinavir, and atazanavir in different HIV-1 subtypes.
Year : 2010
Volume : 54
Issue : 7
First Page : 2878
Last Page : 2885
Authors : Lisovsky I, Schader SM, Martinez-Cajas JL, Oliveira M, Moisi D, Wainberg MA.
Abstract : The amino acid at position 36 of the HIV-1 protease differs among various viral subtypes, in that methionine is usually found in subtype B viruses but isoleucine is common in other subtypes. This polymorphism is associated with higher rates of treatment failure involving protease inhibitors (PIs) in non-subtype B-infected patients. To investigate this, we generated genetically homogeneous wild-type viruses from subtype B, subtype C, and CRF02_AG full-length molecular clones and showed that subtype C and CRF02_AG I36 viruses exhibited higher levels of resistance to various PIs than their respective M36 counterparts, while the opposite was observed for subtype B viruses. Selections for resistance with each variant were performed with nelfinavir (NFV), lopinavir (LPV), and atazanavir (ATV). Sequence analysis of the protease gene at week 35 revealed that the major NFV resistance mutation D30N emerged in NFV-selected subtype B viruses and in I36 subtype C viruses, despite polymorphic variation. A unique mutational pattern developed in subtype C M36 viruses selected with NFV or ATV. The presence of I47A in LPV-selected I36 CRF02_AG virus conferred higher-level resistance than L76V in LPV-selected M36 CRF02_AG virus. Phenotypic analysis revealed a >1,000-fold increase in NFV resistance in I36 subtype C NFV-selected virus with no apparent impact on viral replication capacity. Thus, the position 36 polymorphism in the HIV-1 protease appears to have a differential effect on both drug susceptibility and the viral replication capacity, depending on both the viral subtype and the drug being evaluated.
|
Antiviral activity against wild type HIV1 subtype C infected in human cord blood mononuclear cells assessed as inhibition of viral replication after 48 hrs by luciferase reporter gene assay
|
Human immunodeficiency virus 1
|
1.67
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : HIV-1 protease codon 36 polymorphisms and differential development of resistance to nelfinavir, lopinavir, and atazanavir in different HIV-1 subtypes.
Year : 2010
Volume : 54
Issue : 7
First Page : 2878
Last Page : 2885
Authors : Lisovsky I, Schader SM, Martinez-Cajas JL, Oliveira M, Moisi D, Wainberg MA.
Abstract : The amino acid at position 36 of the HIV-1 protease differs among various viral subtypes, in that methionine is usually found in subtype B viruses but isoleucine is common in other subtypes. This polymorphism is associated with higher rates of treatment failure involving protease inhibitors (PIs) in non-subtype B-infected patients. To investigate this, we generated genetically homogeneous wild-type viruses from subtype B, subtype C, and CRF02_AG full-length molecular clones and showed that subtype C and CRF02_AG I36 viruses exhibited higher levels of resistance to various PIs than their respective M36 counterparts, while the opposite was observed for subtype B viruses. Selections for resistance with each variant were performed with nelfinavir (NFV), lopinavir (LPV), and atazanavir (ATV). Sequence analysis of the protease gene at week 35 revealed that the major NFV resistance mutation D30N emerged in NFV-selected subtype B viruses and in I36 subtype C viruses, despite polymorphic variation. A unique mutational pattern developed in subtype C M36 viruses selected with NFV or ATV. The presence of I47A in LPV-selected I36 CRF02_AG virus conferred higher-level resistance than L76V in LPV-selected M36 CRF02_AG virus. Phenotypic analysis revealed a >1,000-fold increase in NFV resistance in I36 subtype C NFV-selected virus with no apparent impact on viral replication capacity. Thus, the position 36 polymorphism in the HIV-1 protease appears to have a differential effect on both drug susceptibility and the viral replication capacity, depending on both the viral subtype and the drug being evaluated.
|
Antiviral activity against HIV1 subtype C harboring protease L23I, M46I, L89T mutant gene and polymorphism at M36 position infected in human cord blood mononuclear cells assessed as inhibition of viral replication after 48 hrs by luciferase reporter gene assay
|
Human immunodeficiency virus 1
|
272.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : HIV-1 protease codon 36 polymorphisms and differential development of resistance to nelfinavir, lopinavir, and atazanavir in different HIV-1 subtypes.
Year : 2010
Volume : 54
Issue : 7
First Page : 2878
Last Page : 2885
Authors : Lisovsky I, Schader SM, Martinez-Cajas JL, Oliveira M, Moisi D, Wainberg MA.
Abstract : The amino acid at position 36 of the HIV-1 protease differs among various viral subtypes, in that methionine is usually found in subtype B viruses but isoleucine is common in other subtypes. This polymorphism is associated with higher rates of treatment failure involving protease inhibitors (PIs) in non-subtype B-infected patients. To investigate this, we generated genetically homogeneous wild-type viruses from subtype B, subtype C, and CRF02_AG full-length molecular clones and showed that subtype C and CRF02_AG I36 viruses exhibited higher levels of resistance to various PIs than their respective M36 counterparts, while the opposite was observed for subtype B viruses. Selections for resistance with each variant were performed with nelfinavir (NFV), lopinavir (LPV), and atazanavir (ATV). Sequence analysis of the protease gene at week 35 revealed that the major NFV resistance mutation D30N emerged in NFV-selected subtype B viruses and in I36 subtype C viruses, despite polymorphic variation. A unique mutational pattern developed in subtype C M36 viruses selected with NFV or ATV. The presence of I47A in LPV-selected I36 CRF02_AG virus conferred higher-level resistance than L76V in LPV-selected M36 CRF02_AG virus. Phenotypic analysis revealed a >1,000-fold increase in NFV resistance in I36 subtype C NFV-selected virus with no apparent impact on viral replication capacity. Thus, the position 36 polymorphism in the HIV-1 protease appears to have a differential effect on both drug susceptibility and the viral replication capacity, depending on both the viral subtype and the drug being evaluated.
|
Antiviral activity against wild type HIV1 subtype CRF02_AG infected in human cord blood mononuclear cells assessed as inhibition of viral replication after 48 hrs by luciferase reporter gene assay
|
Human immunodeficiency virus 1
|
5.7
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : HIV-1 protease codon 36 polymorphisms and differential development of resistance to nelfinavir, lopinavir, and atazanavir in different HIV-1 subtypes.
Year : 2010
Volume : 54
Issue : 7
First Page : 2878
Last Page : 2885
Authors : Lisovsky I, Schader SM, Martinez-Cajas JL, Oliveira M, Moisi D, Wainberg MA.
Abstract : The amino acid at position 36 of the HIV-1 protease differs among various viral subtypes, in that methionine is usually found in subtype B viruses but isoleucine is common in other subtypes. This polymorphism is associated with higher rates of treatment failure involving protease inhibitors (PIs) in non-subtype B-infected patients. To investigate this, we generated genetically homogeneous wild-type viruses from subtype B, subtype C, and CRF02_AG full-length molecular clones and showed that subtype C and CRF02_AG I36 viruses exhibited higher levels of resistance to various PIs than their respective M36 counterparts, while the opposite was observed for subtype B viruses. Selections for resistance with each variant were performed with nelfinavir (NFV), lopinavir (LPV), and atazanavir (ATV). Sequence analysis of the protease gene at week 35 revealed that the major NFV resistance mutation D30N emerged in NFV-selected subtype B viruses and in I36 subtype C viruses, despite polymorphic variation. A unique mutational pattern developed in subtype C M36 viruses selected with NFV or ATV. The presence of I47A in LPV-selected I36 CRF02_AG virus conferred higher-level resistance than L76V in LPV-selected M36 CRF02_AG virus. Phenotypic analysis revealed a >1,000-fold increase in NFV resistance in I36 subtype C NFV-selected virus with no apparent impact on viral replication capacity. Thus, the position 36 polymorphism in the HIV-1 protease appears to have a differential effect on both drug susceptibility and the viral replication capacity, depending on both the viral subtype and the drug being evaluated.
|
Antiviral activity against HIV1 subtype CRF02_AG harboring protease L33I, M46I, A71T mutant gene and polymorphism at M36 position infected in human cord blood mononuclear cells assessed as inhibition of viral replication after 48 hrs by luciferase reporter gene assay
|
Human immunodeficiency virus 1
|
202.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : HIV-1 protease codon 36 polymorphisms and differential development of resistance to nelfinavir, lopinavir, and atazanavir in different HIV-1 subtypes.
Year : 2010
Volume : 54
Issue : 7
First Page : 2878
Last Page : 2885
Authors : Lisovsky I, Schader SM, Martinez-Cajas JL, Oliveira M, Moisi D, Wainberg MA.
Abstract : The amino acid at position 36 of the HIV-1 protease differs among various viral subtypes, in that methionine is usually found in subtype B viruses but isoleucine is common in other subtypes. This polymorphism is associated with higher rates of treatment failure involving protease inhibitors (PIs) in non-subtype B-infected patients. To investigate this, we generated genetically homogeneous wild-type viruses from subtype B, subtype C, and CRF02_AG full-length molecular clones and showed that subtype C and CRF02_AG I36 viruses exhibited higher levels of resistance to various PIs than their respective M36 counterparts, while the opposite was observed for subtype B viruses. Selections for resistance with each variant were performed with nelfinavir (NFV), lopinavir (LPV), and atazanavir (ATV). Sequence analysis of the protease gene at week 35 revealed that the major NFV resistance mutation D30N emerged in NFV-selected subtype B viruses and in I36 subtype C viruses, despite polymorphic variation. A unique mutational pattern developed in subtype C M36 viruses selected with NFV or ATV. The presence of I47A in LPV-selected I36 CRF02_AG virus conferred higher-level resistance than L76V in LPV-selected M36 CRF02_AG virus. Phenotypic analysis revealed a >1,000-fold increase in NFV resistance in I36 subtype C NFV-selected virus with no apparent impact on viral replication capacity. Thus, the position 36 polymorphism in the HIV-1 protease appears to have a differential effect on both drug susceptibility and the viral replication capacity, depending on both the viral subtype and the drug being evaluated.
|
Antiviral activity against HIV1 subtype CRF02_AG harboring protease polymorphism at I36 position and M46 mutant gene infected in human cord blood mononuclear cells assessed as inhibition of viral replication after 48 hrs by luciferase reporter gene assay
|
Human immunodeficiency virus 1
|
55.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : HIV-1 protease codon 36 polymorphisms and differential development of resistance to nelfinavir, lopinavir, and atazanavir in different HIV-1 subtypes.
Year : 2010
Volume : 54
Issue : 7
First Page : 2878
Last Page : 2885
Authors : Lisovsky I, Schader SM, Martinez-Cajas JL, Oliveira M, Moisi D, Wainberg MA.
Abstract : The amino acid at position 36 of the HIV-1 protease differs among various viral subtypes, in that methionine is usually found in subtype B viruses but isoleucine is common in other subtypes. This polymorphism is associated with higher rates of treatment failure involving protease inhibitors (PIs) in non-subtype B-infected patients. To investigate this, we generated genetically homogeneous wild-type viruses from subtype B, subtype C, and CRF02_AG full-length molecular clones and showed that subtype C and CRF02_AG I36 viruses exhibited higher levels of resistance to various PIs than their respective M36 counterparts, while the opposite was observed for subtype B viruses. Selections for resistance with each variant were performed with nelfinavir (NFV), lopinavir (LPV), and atazanavir (ATV). Sequence analysis of the protease gene at week 35 revealed that the major NFV resistance mutation D30N emerged in NFV-selected subtype B viruses and in I36 subtype C viruses, despite polymorphic variation. A unique mutational pattern developed in subtype C M36 viruses selected with NFV or ATV. The presence of I47A in LPV-selected I36 CRF02_AG virus conferred higher-level resistance than L76V in LPV-selected M36 CRF02_AG virus. Phenotypic analysis revealed a >1,000-fold increase in NFV resistance in I36 subtype C NFV-selected virus with no apparent impact on viral replication capacity. Thus, the position 36 polymorphism in the HIV-1 protease appears to have a differential effect on both drug susceptibility and the viral replication capacity, depending on both the viral subtype and the drug being evaluated.
|
Antiviral activity against HIV1 LAI infected in human MT2 cells after 7 days by MTT assay
|
Human immunodeficiency virus
|
23.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : GRL-02031, a novel nonpeptidic protease inhibitor (PI) containing a stereochemically defined fused cyclopentanyltetrahydrofuran potent against multi-PI-resistant human immunodeficiency virus type 1 in vitro.
Year : 2009
Volume : 53
Issue : 3
First Page : 997
Last Page : 1006
Authors : Koh Y, Das D, Leschenko S, Nakata H, Ogata-Aoki H, Amano M, Nakayama M, Ghosh AK, Mitsuya H.
Abstract : We generated a novel nonpeptidic protease inhibitor (PI), GRL-02031, by incorporating a stereochemically defined fused cyclopentanyltetrahydrofuran (Cp-THF) which exerted potent activity against a wide spectrum of human immunodeficiency virus type 1 (HIV-1) isolates, including multidrug-resistant HIV-1 variants. GRL-02031 was highly potent against laboratory HIV-1 strains and primary clinical isolates, including subtypes A, B, C, and E (50% effective concentration [EC(50)] range, 0.015 to 0.038 microM), with minimal cytotoxicity (50% cytotoxic concentration, >100 microM in CD4(+) MT-2 cells), although it was less active against two HIV-2 strains (HIV-2(EHO) and HIV-2(ROD)) (EC(50), approximately 0.60 microM) than against HIV-1 strains. GRL-02031 at relatively low concentrations blocked the infection and replication of each of the HIV-1(NL4-3) variants exposed to and selected by up to 5 microM of saquinavir, amprenavir, indinavir, nelfinavir, or ritonavir and 1 microM of lopinavir or atazanavir (EC(50) range, 0.036 to 0.14 microM). GRL-02031 was also potent against multi-PI-resistant clinical HIV-1 variants isolated from patients who had no response to the conventional antiretroviral regimens that then existed, with EC(50)s ranging from 0.014 to 0.042 microM (changes in the EC(50)s were less than twofold the EC(50) for wild-type HIV-1). Upon selection of HIV-1(NL4-3) in the presence of GRL-02031, mutants carrying L10F, L33F, M46I, I47V, Q58E, V82I, I84V, and I85V in the protease-encoding region and G62R (within p17), L363M (p24-p2 cleavage site), R409K (within p7), and I437T (p7-p1 cleavage site) in the gag-encoding region emerged. GRL-02031 was potent against a variety of HIV-1(NL4-3)-based molecular infectious clones containing a single primary mutation reported previously or a combination of such mutations, although it was slightly less active against HIV-1 variants containing consecutive amino acid substitutions: M46I and I47V or I84V and I85V. Structural modeling analysis demonstrated a distinct bimodal binding of GRL-02031 to protease, which may provide advantages to GRL-02031 in blocking the replication of a wide spectrum of HIV-1 variants resistant to PIs and in delaying the development of resistance of HIV-1 to GRL-02031. The present data warrant the further development of GRL-02031 as a potential therapeutic agent for the treatment of infections with primary and multidrug-resistant HIV-1 variants.
|
Antiviral activity against HIV1 ERS104pre infected in human PHA-PBC assessed as inhibition of p24 Gag protein production by ELISA
|
Human immunodeficiency virus 1
|
16.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : GRL-02031, a novel nonpeptidic protease inhibitor (PI) containing a stereochemically defined fused cyclopentanyltetrahydrofuran potent against multi-PI-resistant human immunodeficiency virus type 1 in vitro.
Year : 2009
Volume : 53
Issue : 3
First Page : 997
Last Page : 1006
Authors : Koh Y, Das D, Leschenko S, Nakata H, Ogata-Aoki H, Amano M, Nakayama M, Ghosh AK, Mitsuya H.
Abstract : We generated a novel nonpeptidic protease inhibitor (PI), GRL-02031, by incorporating a stereochemically defined fused cyclopentanyltetrahydrofuran (Cp-THF) which exerted potent activity against a wide spectrum of human immunodeficiency virus type 1 (HIV-1) isolates, including multidrug-resistant HIV-1 variants. GRL-02031 was highly potent against laboratory HIV-1 strains and primary clinical isolates, including subtypes A, B, C, and E (50% effective concentration [EC(50)] range, 0.015 to 0.038 microM), with minimal cytotoxicity (50% cytotoxic concentration, >100 microM in CD4(+) MT-2 cells), although it was less active against two HIV-2 strains (HIV-2(EHO) and HIV-2(ROD)) (EC(50), approximately 0.60 microM) than against HIV-1 strains. GRL-02031 at relatively low concentrations blocked the infection and replication of each of the HIV-1(NL4-3) variants exposed to and selected by up to 5 microM of saquinavir, amprenavir, indinavir, nelfinavir, or ritonavir and 1 microM of lopinavir or atazanavir (EC(50) range, 0.036 to 0.14 microM). GRL-02031 was also potent against multi-PI-resistant clinical HIV-1 variants isolated from patients who had no response to the conventional antiretroviral regimens that then existed, with EC(50)s ranging from 0.014 to 0.042 microM (changes in the EC(50)s were less than twofold the EC(50) for wild-type HIV-1). Upon selection of HIV-1(NL4-3) in the presence of GRL-02031, mutants carrying L10F, L33F, M46I, I47V, Q58E, V82I, I84V, and I85V in the protease-encoding region and G62R (within p17), L363M (p24-p2 cleavage site), R409K (within p7), and I437T (p7-p1 cleavage site) in the gag-encoding region emerged. GRL-02031 was potent against a variety of HIV-1(NL4-3)-based molecular infectious clones containing a single primary mutation reported previously or a combination of such mutations, although it was slightly less active against HIV-1 variants containing consecutive amino acid substitutions: M46I and I47V or I84V and I85V. Structural modeling analysis demonstrated a distinct bimodal binding of GRL-02031 to protease, which may provide advantages to GRL-02031 in blocking the replication of a wide spectrum of HIV-1 variants resistant to PIs and in delaying the development of resistance of HIV-1 to GRL-02031. The present data warrant the further development of GRL-02031 as a potential therapeutic agent for the treatment of infections with primary and multidrug-resistant HIV-1 variants.
|
Antiviral activity against HIV1 MOKW infected in human PHA-PBC assessed as inhibition of p24 Gag protein production by ELISA
|
Human immunodeficiency virus 1
|
23.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : GRL-02031, a novel nonpeptidic protease inhibitor (PI) containing a stereochemically defined fused cyclopentanyltetrahydrofuran potent against multi-PI-resistant human immunodeficiency virus type 1 in vitro.
Year : 2009
Volume : 53
Issue : 3
First Page : 997
Last Page : 1006
Authors : Koh Y, Das D, Leschenko S, Nakata H, Ogata-Aoki H, Amano M, Nakayama M, Ghosh AK, Mitsuya H.
Abstract : We generated a novel nonpeptidic protease inhibitor (PI), GRL-02031, by incorporating a stereochemically defined fused cyclopentanyltetrahydrofuran (Cp-THF) which exerted potent activity against a wide spectrum of human immunodeficiency virus type 1 (HIV-1) isolates, including multidrug-resistant HIV-1 variants. GRL-02031 was highly potent against laboratory HIV-1 strains and primary clinical isolates, including subtypes A, B, C, and E (50% effective concentration [EC(50)] range, 0.015 to 0.038 microM), with minimal cytotoxicity (50% cytotoxic concentration, >100 microM in CD4(+) MT-2 cells), although it was less active against two HIV-2 strains (HIV-2(EHO) and HIV-2(ROD)) (EC(50), approximately 0.60 microM) than against HIV-1 strains. GRL-02031 at relatively low concentrations blocked the infection and replication of each of the HIV-1(NL4-3) variants exposed to and selected by up to 5 microM of saquinavir, amprenavir, indinavir, nelfinavir, or ritonavir and 1 microM of lopinavir or atazanavir (EC(50) range, 0.036 to 0.14 microM). GRL-02031 was also potent against multi-PI-resistant clinical HIV-1 variants isolated from patients who had no response to the conventional antiretroviral regimens that then existed, with EC(50)s ranging from 0.014 to 0.042 microM (changes in the EC(50)s were less than twofold the EC(50) for wild-type HIV-1). Upon selection of HIV-1(NL4-3) in the presence of GRL-02031, mutants carrying L10F, L33F, M46I, I47V, Q58E, V82I, I84V, and I85V in the protease-encoding region and G62R (within p17), L363M (p24-p2 cleavage site), R409K (within p7), and I437T (p7-p1 cleavage site) in the gag-encoding region emerged. GRL-02031 was potent against a variety of HIV-1(NL4-3)-based molecular infectious clones containing a single primary mutation reported previously or a combination of such mutations, although it was slightly less active against HIV-1 variants containing consecutive amino acid substitutions: M46I and I47V or I84V and I85V. Structural modeling analysis demonstrated a distinct bimodal binding of GRL-02031 to protease, which may provide advantages to GRL-02031 in blocking the replication of a wide spectrum of HIV-1 variants resistant to PIs and in delaying the development of resistance of HIV-1 to GRL-02031. The present data warrant the further development of GRL-02031 as a potential therapeutic agent for the treatment of infections with primary and multidrug-resistant HIV-1 variants.
|
Antiviral activity against HIV1 A harboring L10I/I15V/E35D/N37E/K45R/I54V/L63P/A71V/V82T/L90M/I93L/C95F in protease encoding region infected in human PHA-PBC assessed as inhibition of p24 Gag protein production by ELISA
|
Human immunodeficiency virus 1
|
330.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : GRL-02031, a novel nonpeptidic protease inhibitor (PI) containing a stereochemically defined fused cyclopentanyltetrahydrofuran potent against multi-PI-resistant human immunodeficiency virus type 1 in vitro.
Year : 2009
Volume : 53
Issue : 3
First Page : 997
Last Page : 1006
Authors : Koh Y, Das D, Leschenko S, Nakata H, Ogata-Aoki H, Amano M, Nakayama M, Ghosh AK, Mitsuya H.
Abstract : We generated a novel nonpeptidic protease inhibitor (PI), GRL-02031, by incorporating a stereochemically defined fused cyclopentanyltetrahydrofuran (Cp-THF) which exerted potent activity against a wide spectrum of human immunodeficiency virus type 1 (HIV-1) isolates, including multidrug-resistant HIV-1 variants. GRL-02031 was highly potent against laboratory HIV-1 strains and primary clinical isolates, including subtypes A, B, C, and E (50% effective concentration [EC(50)] range, 0.015 to 0.038 microM), with minimal cytotoxicity (50% cytotoxic concentration, >100 microM in CD4(+) MT-2 cells), although it was less active against two HIV-2 strains (HIV-2(EHO) and HIV-2(ROD)) (EC(50), approximately 0.60 microM) than against HIV-1 strains. GRL-02031 at relatively low concentrations blocked the infection and replication of each of the HIV-1(NL4-3) variants exposed to and selected by up to 5 microM of saquinavir, amprenavir, indinavir, nelfinavir, or ritonavir and 1 microM of lopinavir or atazanavir (EC(50) range, 0.036 to 0.14 microM). GRL-02031 was also potent against multi-PI-resistant clinical HIV-1 variants isolated from patients who had no response to the conventional antiretroviral regimens that then existed, with EC(50)s ranging from 0.014 to 0.042 microM (changes in the EC(50)s were less than twofold the EC(50) for wild-type HIV-1). Upon selection of HIV-1(NL4-3) in the presence of GRL-02031, mutants carrying L10F, L33F, M46I, I47V, Q58E, V82I, I84V, and I85V in the protease-encoding region and G62R (within p17), L363M (p24-p2 cleavage site), R409K (within p7), and I437T (p7-p1 cleavage site) in the gag-encoding region emerged. GRL-02031 was potent against a variety of HIV-1(NL4-3)-based molecular infectious clones containing a single primary mutation reported previously or a combination of such mutations, although it was slightly less active against HIV-1 variants containing consecutive amino acid substitutions: M46I and I47V or I84V and I85V. Structural modeling analysis demonstrated a distinct bimodal binding of GRL-02031 to protease, which may provide advantages to GRL-02031 in blocking the replication of a wide spectrum of HIV-1 variants resistant to PIs and in delaying the development of resistance of HIV-1 to GRL-02031. The present data warrant the further development of GRL-02031 as a potential therapeutic agent for the treatment of infections with primary and multidrug-resistant HIV-1 variants.
|
Antiviral activity against HIV1 C harboring L10I/I15V/K20R/L24I/M36I/M46L/I54V/I62V/L63P/K70Q/V82A/L89M in protease encoding region infected in human PHA-PBC assessed as inhibition of p24 Gag protein production by ELISA
|
Human immunodeficiency virus 1
|
360.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : GRL-02031, a novel nonpeptidic protease inhibitor (PI) containing a stereochemically defined fused cyclopentanyltetrahydrofuran potent against multi-PI-resistant human immunodeficiency virus type 1 in vitro.
Year : 2009
Volume : 53
Issue : 3
First Page : 997
Last Page : 1006
Authors : Koh Y, Das D, Leschenko S, Nakata H, Ogata-Aoki H, Amano M, Nakayama M, Ghosh AK, Mitsuya H.
Abstract : We generated a novel nonpeptidic protease inhibitor (PI), GRL-02031, by incorporating a stereochemically defined fused cyclopentanyltetrahydrofuran (Cp-THF) which exerted potent activity against a wide spectrum of human immunodeficiency virus type 1 (HIV-1) isolates, including multidrug-resistant HIV-1 variants. GRL-02031 was highly potent against laboratory HIV-1 strains and primary clinical isolates, including subtypes A, B, C, and E (50% effective concentration [EC(50)] range, 0.015 to 0.038 microM), with minimal cytotoxicity (50% cytotoxic concentration, >100 microM in CD4(+) MT-2 cells), although it was less active against two HIV-2 strains (HIV-2(EHO) and HIV-2(ROD)) (EC(50), approximately 0.60 microM) than against HIV-1 strains. GRL-02031 at relatively low concentrations blocked the infection and replication of each of the HIV-1(NL4-3) variants exposed to and selected by up to 5 microM of saquinavir, amprenavir, indinavir, nelfinavir, or ritonavir and 1 microM of lopinavir or atazanavir (EC(50) range, 0.036 to 0.14 microM). GRL-02031 was also potent against multi-PI-resistant clinical HIV-1 variants isolated from patients who had no response to the conventional antiretroviral regimens that then existed, with EC(50)s ranging from 0.014 to 0.042 microM (changes in the EC(50)s were less than twofold the EC(50) for wild-type HIV-1). Upon selection of HIV-1(NL4-3) in the presence of GRL-02031, mutants carrying L10F, L33F, M46I, I47V, Q58E, V82I, I84V, and I85V in the protease-encoding region and G62R (within p17), L363M (p24-p2 cleavage site), R409K (within p7), and I437T (p7-p1 cleavage site) in the gag-encoding region emerged. GRL-02031 was potent against a variety of HIV-1(NL4-3)-based molecular infectious clones containing a single primary mutation reported previously or a combination of such mutations, although it was slightly less active against HIV-1 variants containing consecutive amino acid substitutions: M46I and I47V or I84V and I85V. Structural modeling analysis demonstrated a distinct bimodal binding of GRL-02031 to protease, which may provide advantages to GRL-02031 in blocking the replication of a wide spectrum of HIV-1 variants resistant to PIs and in delaying the development of resistance of HIV-1 to GRL-02031. The present data warrant the further development of GRL-02031 as a potential therapeutic agent for the treatment of infections with primary and multidrug-resistant HIV-1 variants.
|
Antiviral activity against HIV1 G harboring L10I/V11I/T12E/I15V/L19I/R41K/M46L/L63P/A71T/V82A/L90M in protease encoding region infected in human PHA-PBC assessed as inhibition of p24 Gag protein production by ELISA
|
Human immunodeficiency virus 1
|
230.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : GRL-02031, a novel nonpeptidic protease inhibitor (PI) containing a stereochemically defined fused cyclopentanyltetrahydrofuran potent against multi-PI-resistant human immunodeficiency virus type 1 in vitro.
Year : 2009
Volume : 53
Issue : 3
First Page : 997
Last Page : 1006
Authors : Koh Y, Das D, Leschenko S, Nakata H, Ogata-Aoki H, Amano M, Nakayama M, Ghosh AK, Mitsuya H.
Abstract : We generated a novel nonpeptidic protease inhibitor (PI), GRL-02031, by incorporating a stereochemically defined fused cyclopentanyltetrahydrofuran (Cp-THF) which exerted potent activity against a wide spectrum of human immunodeficiency virus type 1 (HIV-1) isolates, including multidrug-resistant HIV-1 variants. GRL-02031 was highly potent against laboratory HIV-1 strains and primary clinical isolates, including subtypes A, B, C, and E (50% effective concentration [EC(50)] range, 0.015 to 0.038 microM), with minimal cytotoxicity (50% cytotoxic concentration, >100 microM in CD4(+) MT-2 cells), although it was less active against two HIV-2 strains (HIV-2(EHO) and HIV-2(ROD)) (EC(50), approximately 0.60 microM) than against HIV-1 strains. GRL-02031 at relatively low concentrations blocked the infection and replication of each of the HIV-1(NL4-3) variants exposed to and selected by up to 5 microM of saquinavir, amprenavir, indinavir, nelfinavir, or ritonavir and 1 microM of lopinavir or atazanavir (EC(50) range, 0.036 to 0.14 microM). GRL-02031 was also potent against multi-PI-resistant clinical HIV-1 variants isolated from patients who had no response to the conventional antiretroviral regimens that then existed, with EC(50)s ranging from 0.014 to 0.042 microM (changes in the EC(50)s were less than twofold the EC(50) for wild-type HIV-1). Upon selection of HIV-1(NL4-3) in the presence of GRL-02031, mutants carrying L10F, L33F, M46I, I47V, Q58E, V82I, I84V, and I85V in the protease-encoding region and G62R (within p17), L363M (p24-p2 cleavage site), R409K (within p7), and I437T (p7-p1 cleavage site) in the gag-encoding region emerged. GRL-02031 was potent against a variety of HIV-1(NL4-3)-based molecular infectious clones containing a single primary mutation reported previously or a combination of such mutations, although it was slightly less active against HIV-1 variants containing consecutive amino acid substitutions: M46I and I47V or I84V and I85V. Structural modeling analysis demonstrated a distinct bimodal binding of GRL-02031 to protease, which may provide advantages to GRL-02031 in blocking the replication of a wide spectrum of HIV-1 variants resistant to PIs and in delaying the development of resistance of HIV-1 to GRL-02031. The present data warrant the further development of GRL-02031 as a potential therapeutic agent for the treatment of infections with primary and multidrug-resistant HIV-1 variants.
|
Antiviral activity against HIV1 NL4-3 infected in human MT4 cells assessed as inhibition of p24 gag protein production by ELISA
|
Human immunodeficiency virus 1
|
18.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : GRL-02031, a novel nonpeptidic protease inhibitor (PI) containing a stereochemically defined fused cyclopentanyltetrahydrofuran potent against multi-PI-resistant human immunodeficiency virus type 1 in vitro.
Year : 2009
Volume : 53
Issue : 3
First Page : 997
Last Page : 1006
Authors : Koh Y, Das D, Leschenko S, Nakata H, Ogata-Aoki H, Amano M, Nakayama M, Ghosh AK, Mitsuya H.
Abstract : We generated a novel nonpeptidic protease inhibitor (PI), GRL-02031, by incorporating a stereochemically defined fused cyclopentanyltetrahydrofuran (Cp-THF) which exerted potent activity against a wide spectrum of human immunodeficiency virus type 1 (HIV-1) isolates, including multidrug-resistant HIV-1 variants. GRL-02031 was highly potent against laboratory HIV-1 strains and primary clinical isolates, including subtypes A, B, C, and E (50% effective concentration [EC(50)] range, 0.015 to 0.038 microM), with minimal cytotoxicity (50% cytotoxic concentration, >100 microM in CD4(+) MT-2 cells), although it was less active against two HIV-2 strains (HIV-2(EHO) and HIV-2(ROD)) (EC(50), approximately 0.60 microM) than against HIV-1 strains. GRL-02031 at relatively low concentrations blocked the infection and replication of each of the HIV-1(NL4-3) variants exposed to and selected by up to 5 microM of saquinavir, amprenavir, indinavir, nelfinavir, or ritonavir and 1 microM of lopinavir or atazanavir (EC(50) range, 0.036 to 0.14 microM). GRL-02031 was also potent against multi-PI-resistant clinical HIV-1 variants isolated from patients who had no response to the conventional antiretroviral regimens that then existed, with EC(50)s ranging from 0.014 to 0.042 microM (changes in the EC(50)s were less than twofold the EC(50) for wild-type HIV-1). Upon selection of HIV-1(NL4-3) in the presence of GRL-02031, mutants carrying L10F, L33F, M46I, I47V, Q58E, V82I, I84V, and I85V in the protease-encoding region and G62R (within p17), L363M (p24-p2 cleavage site), R409K (within p7), and I437T (p7-p1 cleavage site) in the gag-encoding region emerged. GRL-02031 was potent against a variety of HIV-1(NL4-3)-based molecular infectious clones containing a single primary mutation reported previously or a combination of such mutations, although it was slightly less active against HIV-1 variants containing consecutive amino acid substitutions: M46I and I47V or I84V and I85V. Structural modeling analysis demonstrated a distinct bimodal binding of GRL-02031 to protease, which may provide advantages to GRL-02031 in blocking the replication of a wide spectrum of HIV-1 variants resistant to PIs and in delaying the development of resistance of HIV-1 to GRL-02031. The present data warrant the further development of GRL-02031 as a potential therapeutic agent for the treatment of infections with primary and multidrug-resistant HIV-1 variants.
|
Antiviral activity against HIV1 NL4-3 harboring L10I/G48V/I54V/L90M amino acid substitution in protease encoding region infected in human MT4 cells assessed as inhibition of p24 Gag protein production selected at 5 uM of saquinavir by ELISA
|
Human immunodeficiency virus 1
|
320.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : GRL-02031, a novel nonpeptidic protease inhibitor (PI) containing a stereochemically defined fused cyclopentanyltetrahydrofuran potent against multi-PI-resistant human immunodeficiency virus type 1 in vitro.
Year : 2009
Volume : 53
Issue : 3
First Page : 997
Last Page : 1006
Authors : Koh Y, Das D, Leschenko S, Nakata H, Ogata-Aoki H, Amano M, Nakayama M, Ghosh AK, Mitsuya H.
Abstract : We generated a novel nonpeptidic protease inhibitor (PI), GRL-02031, by incorporating a stereochemically defined fused cyclopentanyltetrahydrofuran (Cp-THF) which exerted potent activity against a wide spectrum of human immunodeficiency virus type 1 (HIV-1) isolates, including multidrug-resistant HIV-1 variants. GRL-02031 was highly potent against laboratory HIV-1 strains and primary clinical isolates, including subtypes A, B, C, and E (50% effective concentration [EC(50)] range, 0.015 to 0.038 microM), with minimal cytotoxicity (50% cytotoxic concentration, >100 microM in CD4(+) MT-2 cells), although it was less active against two HIV-2 strains (HIV-2(EHO) and HIV-2(ROD)) (EC(50), approximately 0.60 microM) than against HIV-1 strains. GRL-02031 at relatively low concentrations blocked the infection and replication of each of the HIV-1(NL4-3) variants exposed to and selected by up to 5 microM of saquinavir, amprenavir, indinavir, nelfinavir, or ritonavir and 1 microM of lopinavir or atazanavir (EC(50) range, 0.036 to 0.14 microM). GRL-02031 was also potent against multi-PI-resistant clinical HIV-1 variants isolated from patients who had no response to the conventional antiretroviral regimens that then existed, with EC(50)s ranging from 0.014 to 0.042 microM (changes in the EC(50)s were less than twofold the EC(50) for wild-type HIV-1). Upon selection of HIV-1(NL4-3) in the presence of GRL-02031, mutants carrying L10F, L33F, M46I, I47V, Q58E, V82I, I84V, and I85V in the protease-encoding region and G62R (within p17), L363M (p24-p2 cleavage site), R409K (within p7), and I437T (p7-p1 cleavage site) in the gag-encoding region emerged. GRL-02031 was potent against a variety of HIV-1(NL4-3)-based molecular infectious clones containing a single primary mutation reported previously or a combination of such mutations, although it was slightly less active against HIV-1 variants containing consecutive amino acid substitutions: M46I and I47V or I84V and I85V. Structural modeling analysis demonstrated a distinct bimodal binding of GRL-02031 to protease, which may provide advantages to GRL-02031 in blocking the replication of a wide spectrum of HIV-1 variants resistant to PIs and in delaying the development of resistance of HIV-1 to GRL-02031. The present data warrant the further development of GRL-02031 as a potential therapeutic agent for the treatment of infections with primary and multidrug-resistant HIV-1 variants.
|
Antiviral activity against HIV1 NL4-3 harboring L10F/V32I/M46I/I54M//A71V/I84V amino acid substitution in protease encoding region infected in human MT4 cells assessed as inhibition of p24 Gag protein production selected at 5 uM of amprenavir by ELISA
|
Human immunodeficiency virus 1
|
170.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : GRL-02031, a novel nonpeptidic protease inhibitor (PI) containing a stereochemically defined fused cyclopentanyltetrahydrofuran potent against multi-PI-resistant human immunodeficiency virus type 1 in vitro.
Year : 2009
Volume : 53
Issue : 3
First Page : 997
Last Page : 1006
Authors : Koh Y, Das D, Leschenko S, Nakata H, Ogata-Aoki H, Amano M, Nakayama M, Ghosh AK, Mitsuya H.
Abstract : We generated a novel nonpeptidic protease inhibitor (PI), GRL-02031, by incorporating a stereochemically defined fused cyclopentanyltetrahydrofuran (Cp-THF) which exerted potent activity against a wide spectrum of human immunodeficiency virus type 1 (HIV-1) isolates, including multidrug-resistant HIV-1 variants. GRL-02031 was highly potent against laboratory HIV-1 strains and primary clinical isolates, including subtypes A, B, C, and E (50% effective concentration [EC(50)] range, 0.015 to 0.038 microM), with minimal cytotoxicity (50% cytotoxic concentration, >100 microM in CD4(+) MT-2 cells), although it was less active against two HIV-2 strains (HIV-2(EHO) and HIV-2(ROD)) (EC(50), approximately 0.60 microM) than against HIV-1 strains. GRL-02031 at relatively low concentrations blocked the infection and replication of each of the HIV-1(NL4-3) variants exposed to and selected by up to 5 microM of saquinavir, amprenavir, indinavir, nelfinavir, or ritonavir and 1 microM of lopinavir or atazanavir (EC(50) range, 0.036 to 0.14 microM). GRL-02031 was also potent against multi-PI-resistant clinical HIV-1 variants isolated from patients who had no response to the conventional antiretroviral regimens that then existed, with EC(50)s ranging from 0.014 to 0.042 microM (changes in the EC(50)s were less than twofold the EC(50) for wild-type HIV-1). Upon selection of HIV-1(NL4-3) in the presence of GRL-02031, mutants carrying L10F, L33F, M46I, I47V, Q58E, V82I, I84V, and I85V in the protease-encoding region and G62R (within p17), L363M (p24-p2 cleavage site), R409K (within p7), and I437T (p7-p1 cleavage site) in the gag-encoding region emerged. GRL-02031 was potent against a variety of HIV-1(NL4-3)-based molecular infectious clones containing a single primary mutation reported previously or a combination of such mutations, although it was slightly less active against HIV-1 variants containing consecutive amino acid substitutions: M46I and I47V or I84V and I85V. Structural modeling analysis demonstrated a distinct bimodal binding of GRL-02031 to protease, which may provide advantages to GRL-02031 in blocking the replication of a wide spectrum of HIV-1 variants resistant to PIs and in delaying the development of resistance of HIV-1 to GRL-02031. The present data warrant the further development of GRL-02031 as a potential therapeutic agent for the treatment of infections with primary and multidrug-resistant HIV-1 variants.
|
Antiviral activity against HIV1 NL4-3 harboring L10F/L24I/M46I/L63P/A71V/G73S/V82T amino acid substitution in protease encoding region infected in human MT4 cells assessed as inhibition of p24 Gag protein production selected at 5 uM of indinavir by ELISA
|
Human immunodeficiency virus 1
|
650.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : GRL-02031, a novel nonpeptidic protease inhibitor (PI) containing a stereochemically defined fused cyclopentanyltetrahydrofuran potent against multi-PI-resistant human immunodeficiency virus type 1 in vitro.
Year : 2009
Volume : 53
Issue : 3
First Page : 997
Last Page : 1006
Authors : Koh Y, Das D, Leschenko S, Nakata H, Ogata-Aoki H, Amano M, Nakayama M, Ghosh AK, Mitsuya H.
Abstract : We generated a novel nonpeptidic protease inhibitor (PI), GRL-02031, by incorporating a stereochemically defined fused cyclopentanyltetrahydrofuran (Cp-THF) which exerted potent activity against a wide spectrum of human immunodeficiency virus type 1 (HIV-1) isolates, including multidrug-resistant HIV-1 variants. GRL-02031 was highly potent against laboratory HIV-1 strains and primary clinical isolates, including subtypes A, B, C, and E (50% effective concentration [EC(50)] range, 0.015 to 0.038 microM), with minimal cytotoxicity (50% cytotoxic concentration, >100 microM in CD4(+) MT-2 cells), although it was less active against two HIV-2 strains (HIV-2(EHO) and HIV-2(ROD)) (EC(50), approximately 0.60 microM) than against HIV-1 strains. GRL-02031 at relatively low concentrations blocked the infection and replication of each of the HIV-1(NL4-3) variants exposed to and selected by up to 5 microM of saquinavir, amprenavir, indinavir, nelfinavir, or ritonavir and 1 microM of lopinavir or atazanavir (EC(50) range, 0.036 to 0.14 microM). GRL-02031 was also potent against multi-PI-resistant clinical HIV-1 variants isolated from patients who had no response to the conventional antiretroviral regimens that then existed, with EC(50)s ranging from 0.014 to 0.042 microM (changes in the EC(50)s were less than twofold the EC(50) for wild-type HIV-1). Upon selection of HIV-1(NL4-3) in the presence of GRL-02031, mutants carrying L10F, L33F, M46I, I47V, Q58E, V82I, I84V, and I85V in the protease-encoding region and G62R (within p17), L363M (p24-p2 cleavage site), R409K (within p7), and I437T (p7-p1 cleavage site) in the gag-encoding region emerged. GRL-02031 was potent against a variety of HIV-1(NL4-3)-based molecular infectious clones containing a single primary mutation reported previously or a combination of such mutations, although it was slightly less active against HIV-1 variants containing consecutive amino acid substitutions: M46I and I47V or I84V and I85V. Structural modeling analysis demonstrated a distinct bimodal binding of GRL-02031 to protease, which may provide advantages to GRL-02031 in blocking the replication of a wide spectrum of HIV-1 variants resistant to PIs and in delaying the development of resistance of HIV-1 to GRL-02031. The present data warrant the further development of GRL-02031 as a potential therapeutic agent for the treatment of infections with primary and multidrug-resistant HIV-1 variants.
|
Antiviral activity against HIV1 NL4-3 harboring M46I/V82F/I84V amino acid substitution in protease encoding region infected in human MT4 cells assessed as inhibition of p24 Gag protein production selected at 5 uM of ritonavir by ELISA
|
Human immunodeficiency virus 1
|
240.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : GRL-02031, a novel nonpeptidic protease inhibitor (PI) containing a stereochemically defined fused cyclopentanyltetrahydrofuran potent against multi-PI-resistant human immunodeficiency virus type 1 in vitro.
Year : 2009
Volume : 53
Issue : 3
First Page : 997
Last Page : 1006
Authors : Koh Y, Das D, Leschenko S, Nakata H, Ogata-Aoki H, Amano M, Nakayama M, Ghosh AK, Mitsuya H.
Abstract : We generated a novel nonpeptidic protease inhibitor (PI), GRL-02031, by incorporating a stereochemically defined fused cyclopentanyltetrahydrofuran (Cp-THF) which exerted potent activity against a wide spectrum of human immunodeficiency virus type 1 (HIV-1) isolates, including multidrug-resistant HIV-1 variants. GRL-02031 was highly potent against laboratory HIV-1 strains and primary clinical isolates, including subtypes A, B, C, and E (50% effective concentration [EC(50)] range, 0.015 to 0.038 microM), with minimal cytotoxicity (50% cytotoxic concentration, >100 microM in CD4(+) MT-2 cells), although it was less active against two HIV-2 strains (HIV-2(EHO) and HIV-2(ROD)) (EC(50), approximately 0.60 microM) than against HIV-1 strains. GRL-02031 at relatively low concentrations blocked the infection and replication of each of the HIV-1(NL4-3) variants exposed to and selected by up to 5 microM of saquinavir, amprenavir, indinavir, nelfinavir, or ritonavir and 1 microM of lopinavir or atazanavir (EC(50) range, 0.036 to 0.14 microM). GRL-02031 was also potent against multi-PI-resistant clinical HIV-1 variants isolated from patients who had no response to the conventional antiretroviral regimens that then existed, with EC(50)s ranging from 0.014 to 0.042 microM (changes in the EC(50)s were less than twofold the EC(50) for wild-type HIV-1). Upon selection of HIV-1(NL4-3) in the presence of GRL-02031, mutants carrying L10F, L33F, M46I, I47V, Q58E, V82I, I84V, and I85V in the protease-encoding region and G62R (within p17), L363M (p24-p2 cleavage site), R409K (within p7), and I437T (p7-p1 cleavage site) in the gag-encoding region emerged. GRL-02031 was potent against a variety of HIV-1(NL4-3)-based molecular infectious clones containing a single primary mutation reported previously or a combination of such mutations, although it was slightly less active against HIV-1 variants containing consecutive amino acid substitutions: M46I and I47V or I84V and I85V. Structural modeling analysis demonstrated a distinct bimodal binding of GRL-02031 to protease, which may provide advantages to GRL-02031 in blocking the replication of a wide spectrum of HIV-1 variants resistant to PIs and in delaying the development of resistance of HIV-1 to GRL-02031. The present data warrant the further development of GRL-02031 as a potential therapeutic agent for the treatment of infections with primary and multidrug-resistant HIV-1 variants.
|
Antiviral activity against HIV1 NL4-3 harboring L10F/M46I/I54V/V82A amino acid substitution in protease encoding region infected in human MT4 cells assessed as inhibition of p24 Gag protein production selected at 1 uM of Lopinavir by ELISA
|
Human immunodeficiency virus 1
|
510.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : GRL-02031, a novel nonpeptidic protease inhibitor (PI) containing a stereochemically defined fused cyclopentanyltetrahydrofuran potent against multi-PI-resistant human immunodeficiency virus type 1 in vitro.
Year : 2009
Volume : 53
Issue : 3
First Page : 997
Last Page : 1006
Authors : Koh Y, Das D, Leschenko S, Nakata H, Ogata-Aoki H, Amano M, Nakayama M, Ghosh AK, Mitsuya H.
Abstract : We generated a novel nonpeptidic protease inhibitor (PI), GRL-02031, by incorporating a stereochemically defined fused cyclopentanyltetrahydrofuran (Cp-THF) which exerted potent activity against a wide spectrum of human immunodeficiency virus type 1 (HIV-1) isolates, including multidrug-resistant HIV-1 variants. GRL-02031 was highly potent against laboratory HIV-1 strains and primary clinical isolates, including subtypes A, B, C, and E (50% effective concentration [EC(50)] range, 0.015 to 0.038 microM), with minimal cytotoxicity (50% cytotoxic concentration, >100 microM in CD4(+) MT-2 cells), although it was less active against two HIV-2 strains (HIV-2(EHO) and HIV-2(ROD)) (EC(50), approximately 0.60 microM) than against HIV-1 strains. GRL-02031 at relatively low concentrations blocked the infection and replication of each of the HIV-1(NL4-3) variants exposed to and selected by up to 5 microM of saquinavir, amprenavir, indinavir, nelfinavir, or ritonavir and 1 microM of lopinavir or atazanavir (EC(50) range, 0.036 to 0.14 microM). GRL-02031 was also potent against multi-PI-resistant clinical HIV-1 variants isolated from patients who had no response to the conventional antiretroviral regimens that then existed, with EC(50)s ranging from 0.014 to 0.042 microM (changes in the EC(50)s were less than twofold the EC(50) for wild-type HIV-1). Upon selection of HIV-1(NL4-3) in the presence of GRL-02031, mutants carrying L10F, L33F, M46I, I47V, Q58E, V82I, I84V, and I85V in the protease-encoding region and G62R (within p17), L363M (p24-p2 cleavage site), R409K (within p7), and I437T (p7-p1 cleavage site) in the gag-encoding region emerged. GRL-02031 was potent against a variety of HIV-1(NL4-3)-based molecular infectious clones containing a single primary mutation reported previously or a combination of such mutations, although it was slightly less active against HIV-1 variants containing consecutive amino acid substitutions: M46I and I47V or I84V and I85V. Structural modeling analysis demonstrated a distinct bimodal binding of GRL-02031 to protease, which may provide advantages to GRL-02031 in blocking the replication of a wide spectrum of HIV-1 variants resistant to PIs and in delaying the development of resistance of HIV-1 to GRL-02031. The present data warrant the further development of GRL-02031 as a potential therapeutic agent for the treatment of infections with primary and multidrug-resistant HIV-1 variants.
|
Antiviral activity against HIV1 NL4-3 harboring L23I/K43I/M46I/I50L/G51A/A71V amino acid substitution in protease encoding region infected in human MT4 cells assessed as inhibition of p24 Gag protein production selected at 1 uM of atazanavir by ELISA
|
Human immunodeficiency virus 1
|
210.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : GRL-02031, a novel nonpeptidic protease inhibitor (PI) containing a stereochemically defined fused cyclopentanyltetrahydrofuran potent against multi-PI-resistant human immunodeficiency virus type 1 in vitro.
Year : 2009
Volume : 53
Issue : 3
First Page : 997
Last Page : 1006
Authors : Koh Y, Das D, Leschenko S, Nakata H, Ogata-Aoki H, Amano M, Nakayama M, Ghosh AK, Mitsuya H.
Abstract : We generated a novel nonpeptidic protease inhibitor (PI), GRL-02031, by incorporating a stereochemically defined fused cyclopentanyltetrahydrofuran (Cp-THF) which exerted potent activity against a wide spectrum of human immunodeficiency virus type 1 (HIV-1) isolates, including multidrug-resistant HIV-1 variants. GRL-02031 was highly potent against laboratory HIV-1 strains and primary clinical isolates, including subtypes A, B, C, and E (50% effective concentration [EC(50)] range, 0.015 to 0.038 microM), with minimal cytotoxicity (50% cytotoxic concentration, >100 microM in CD4(+) MT-2 cells), although it was less active against two HIV-2 strains (HIV-2(EHO) and HIV-2(ROD)) (EC(50), approximately 0.60 microM) than against HIV-1 strains. GRL-02031 at relatively low concentrations blocked the infection and replication of each of the HIV-1(NL4-3) variants exposed to and selected by up to 5 microM of saquinavir, amprenavir, indinavir, nelfinavir, or ritonavir and 1 microM of lopinavir or atazanavir (EC(50) range, 0.036 to 0.14 microM). GRL-02031 was also potent against multi-PI-resistant clinical HIV-1 variants isolated from patients who had no response to the conventional antiretroviral regimens that then existed, with EC(50)s ranging from 0.014 to 0.042 microM (changes in the EC(50)s were less than twofold the EC(50) for wild-type HIV-1). Upon selection of HIV-1(NL4-3) in the presence of GRL-02031, mutants carrying L10F, L33F, M46I, I47V, Q58E, V82I, I84V, and I85V in the protease-encoding region and G62R (within p17), L363M (p24-p2 cleavage site), R409K (within p7), and I437T (p7-p1 cleavage site) in the gag-encoding region emerged. GRL-02031 was potent against a variety of HIV-1(NL4-3)-based molecular infectious clones containing a single primary mutation reported previously or a combination of such mutations, although it was slightly less active against HIV-1 variants containing consecutive amino acid substitutions: M46I and I47V or I84V and I85V. Structural modeling analysis demonstrated a distinct bimodal binding of GRL-02031 to protease, which may provide advantages to GRL-02031 in blocking the replication of a wide spectrum of HIV-1 variants resistant to PIs and in delaying the development of resistance of HIV-1 to GRL-02031. The present data warrant the further development of GRL-02031 as a potential therapeutic agent for the treatment of infections with primary and multidrug-resistant HIV-1 variants.
|
Antiviral activity against HIV1 NL4-3 harboring L10F/L33F/M46I/I47V/Q58E/V82I/I84V/I85V amino acid substitution in protease encoding region infected in human MT4 cells assessed as inhibition of p24 Gag protein production selected at 5 uM of GRL-02031 by ELISA
|
Human immunodeficiency virus 1
|
11.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : GRL-02031, a novel nonpeptidic protease inhibitor (PI) containing a stereochemically defined fused cyclopentanyltetrahydrofuran potent against multi-PI-resistant human immunodeficiency virus type 1 in vitro.
Year : 2009
Volume : 53
Issue : 3
First Page : 997
Last Page : 1006
Authors : Koh Y, Das D, Leschenko S, Nakata H, Ogata-Aoki H, Amano M, Nakayama M, Ghosh AK, Mitsuya H.
Abstract : We generated a novel nonpeptidic protease inhibitor (PI), GRL-02031, by incorporating a stereochemically defined fused cyclopentanyltetrahydrofuran (Cp-THF) which exerted potent activity against a wide spectrum of human immunodeficiency virus type 1 (HIV-1) isolates, including multidrug-resistant HIV-1 variants. GRL-02031 was highly potent against laboratory HIV-1 strains and primary clinical isolates, including subtypes A, B, C, and E (50% effective concentration [EC(50)] range, 0.015 to 0.038 microM), with minimal cytotoxicity (50% cytotoxic concentration, >100 microM in CD4(+) MT-2 cells), although it was less active against two HIV-2 strains (HIV-2(EHO) and HIV-2(ROD)) (EC(50), approximately 0.60 microM) than against HIV-1 strains. GRL-02031 at relatively low concentrations blocked the infection and replication of each of the HIV-1(NL4-3) variants exposed to and selected by up to 5 microM of saquinavir, amprenavir, indinavir, nelfinavir, or ritonavir and 1 microM of lopinavir or atazanavir (EC(50) range, 0.036 to 0.14 microM). GRL-02031 was also potent against multi-PI-resistant clinical HIV-1 variants isolated from patients who had no response to the conventional antiretroviral regimens that then existed, with EC(50)s ranging from 0.014 to 0.042 microM (changes in the EC(50)s were less than twofold the EC(50) for wild-type HIV-1). Upon selection of HIV-1(NL4-3) in the presence of GRL-02031, mutants carrying L10F, L33F, M46I, I47V, Q58E, V82I, I84V, and I85V in the protease-encoding region and G62R (within p17), L363M (p24-p2 cleavage site), R409K (within p7), and I437T (p7-p1 cleavage site) in the gag-encoding region emerged. GRL-02031 was potent against a variety of HIV-1(NL4-3)-based molecular infectious clones containing a single primary mutation reported previously or a combination of such mutations, although it was slightly less active against HIV-1 variants containing consecutive amino acid substitutions: M46I and I47V or I84V and I85V. Structural modeling analysis demonstrated a distinct bimodal binding of GRL-02031 to protease, which may provide advantages to GRL-02031 in blocking the replication of a wide spectrum of HIV-1 variants resistant to PIs and in delaying the development of resistance of HIV-1 to GRL-02031. The present data warrant the further development of GRL-02031 as a potential therapeutic agent for the treatment of infections with primary and multidrug-resistant HIV-1 variants.
|
Antiviral activity against HIV1 NL4-3 infected in HEK293 cells assessed as decrease in virus production at 2 times EC90 after 72 hrs by beta-galactosidase reporter gene assay
|
Human immunodeficiency virus 1
|
76.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : New small-molecule inhibitor class targeting human immunodeficiency virus type 1 virion maturation.
Year : 2009
Volume : 53
Issue : 12
First Page : 5080
Last Page : 5087
Authors : Blair WS, Cao J, Fok-Seang J, Griffin P, Isaacson J, Jackson RL, Murray E, Patick AK, Peng Q, Perros M, Pickford C, Wu H, Butler SL.
Abstract : A new small-molecule inhibitor class that targets virion maturation was identified from a human immunodeficiency virus type 1 (HIV-1) antiviral screen. PF-46396, a representative molecule, exhibits antiviral activity against HIV-1 laboratory strains and clinical isolates in T-cell lines and peripheral blood mononuclear cells (PBMCs). PF-46396 specifically inhibits the processing of capsid (CA)/spacer peptide 1 (SP1) (p25), resulting in the accumulation of CA/SP1 (p25) precursor proteins and blocked maturation of the viral core particle. Viral variants resistant to PF-46396 contain a single amino acid substitution in HIV-1 CA sequences (CAI201V), distal to the CA/SP1 cleavage site in the primary structure, which we demonstrate is sufficient to confer significant resistance to PF-46396 and 3-O-(3',3'-dimethylsuccinyl) betulinic acid (DSB), a previously described maturation inhibitor. Conversely, a single amino substitution in SP1 (SP1A1V), which was previously associated with DSB in vitro resistance, was sufficient to confer resistance to DSB and PF-46396. Further, the CAI201V substitution restored CA/SP1 processing in HIV-1-infected cells treated with PF-46396 or DSB. Our results demonstrate that PF-46396 acts through a mechanism that is similar to DSB to inhibit the maturation of HIV-1 virions. To our knowledge, PF-46396 represents the first small-molecule HIV-1 maturation inhibitor that is distinct in chemical class from betulinic acid-derived maturation inhibitors (e.g., DSB), demonstrating that molecules of diverse chemical classes can inhibit this mechanism.
|
Antiviral activity against wild type HIV1 infected in human HeLa cells assessed as decrease in viral infection after 72 hrs by beta-galactosidase reporter gene assay
|
Human immunodeficiency virus 1
|
16.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : New small-molecule inhibitor class targeting human immunodeficiency virus type 1 virion maturation.
Year : 2009
Volume : 53
Issue : 12
First Page : 5080
Last Page : 5087
Authors : Blair WS, Cao J, Fok-Seang J, Griffin P, Isaacson J, Jackson RL, Murray E, Patick AK, Peng Q, Perros M, Pickford C, Wu H, Butler SL.
Abstract : A new small-molecule inhibitor class that targets virion maturation was identified from a human immunodeficiency virus type 1 (HIV-1) antiviral screen. PF-46396, a representative molecule, exhibits antiviral activity against HIV-1 laboratory strains and clinical isolates in T-cell lines and peripheral blood mononuclear cells (PBMCs). PF-46396 specifically inhibits the processing of capsid (CA)/spacer peptide 1 (SP1) (p25), resulting in the accumulation of CA/SP1 (p25) precursor proteins and blocked maturation of the viral core particle. Viral variants resistant to PF-46396 contain a single amino acid substitution in HIV-1 CA sequences (CAI201V), distal to the CA/SP1 cleavage site in the primary structure, which we demonstrate is sufficient to confer significant resistance to PF-46396 and 3-O-(3',3'-dimethylsuccinyl) betulinic acid (DSB), a previously described maturation inhibitor. Conversely, a single amino substitution in SP1 (SP1A1V), which was previously associated with DSB in vitro resistance, was sufficient to confer resistance to DSB and PF-46396. Further, the CAI201V substitution restored CA/SP1 processing in HIV-1-infected cells treated with PF-46396 or DSB. Our results demonstrate that PF-46396 acts through a mechanism that is similar to DSB to inhibit the maturation of HIV-1 virions. To our knowledge, PF-46396 represents the first small-molecule HIV-1 maturation inhibitor that is distinct in chemical class from betulinic acid-derived maturation inhibitors (e.g., DSB), demonstrating that molecules of diverse chemical classes can inhibit this mechanism.
|
Antiviral activity against HIV1 harboring capsid I201V mutant protein infected in human HeLa cells assessed as decrease in viral infection after 72 hrs by beta-galactosidase reporter gene assay
|
Human immunodeficiency virus 1
|
13.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : New small-molecule inhibitor class targeting human immunodeficiency virus type 1 virion maturation.
Year : 2009
Volume : 53
Issue : 12
First Page : 5080
Last Page : 5087
Authors : Blair WS, Cao J, Fok-Seang J, Griffin P, Isaacson J, Jackson RL, Murray E, Patick AK, Peng Q, Perros M, Pickford C, Wu H, Butler SL.
Abstract : A new small-molecule inhibitor class that targets virion maturation was identified from a human immunodeficiency virus type 1 (HIV-1) antiviral screen. PF-46396, a representative molecule, exhibits antiviral activity against HIV-1 laboratory strains and clinical isolates in T-cell lines and peripheral blood mononuclear cells (PBMCs). PF-46396 specifically inhibits the processing of capsid (CA)/spacer peptide 1 (SP1) (p25), resulting in the accumulation of CA/SP1 (p25) precursor proteins and blocked maturation of the viral core particle. Viral variants resistant to PF-46396 contain a single amino acid substitution in HIV-1 CA sequences (CAI201V), distal to the CA/SP1 cleavage site in the primary structure, which we demonstrate is sufficient to confer significant resistance to PF-46396 and 3-O-(3',3'-dimethylsuccinyl) betulinic acid (DSB), a previously described maturation inhibitor. Conversely, a single amino substitution in SP1 (SP1A1V), which was previously associated with DSB in vitro resistance, was sufficient to confer resistance to DSB and PF-46396. Further, the CAI201V substitution restored CA/SP1 processing in HIV-1-infected cells treated with PF-46396 or DSB. Our results demonstrate that PF-46396 acts through a mechanism that is similar to DSB to inhibit the maturation of HIV-1 virions. To our knowledge, PF-46396 represents the first small-molecule HIV-1 maturation inhibitor that is distinct in chemical class from betulinic acid-derived maturation inhibitors (e.g., DSB), demonstrating that molecules of diverse chemical classes can inhibit this mechanism.
|
Antiviral activity against HIV1 harboring spacer peptide A1V mutant protein infected in human HeLa cells assessed as decrease in viral infection after 72 hrs by beta-galactosidase reporter gene assay
|
Human immunodeficiency virus 1
|
38.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : New small-molecule inhibitor class targeting human immunodeficiency virus type 1 virion maturation.
Year : 2009
Volume : 53
Issue : 12
First Page : 5080
Last Page : 5087
Authors : Blair WS, Cao J, Fok-Seang J, Griffin P, Isaacson J, Jackson RL, Murray E, Patick AK, Peng Q, Perros M, Pickford C, Wu H, Butler SL.
Abstract : A new small-molecule inhibitor class that targets virion maturation was identified from a human immunodeficiency virus type 1 (HIV-1) antiviral screen. PF-46396, a representative molecule, exhibits antiviral activity against HIV-1 laboratory strains and clinical isolates in T-cell lines and peripheral blood mononuclear cells (PBMCs). PF-46396 specifically inhibits the processing of capsid (CA)/spacer peptide 1 (SP1) (p25), resulting in the accumulation of CA/SP1 (p25) precursor proteins and blocked maturation of the viral core particle. Viral variants resistant to PF-46396 contain a single amino acid substitution in HIV-1 CA sequences (CAI201V), distal to the CA/SP1 cleavage site in the primary structure, which we demonstrate is sufficient to confer significant resistance to PF-46396 and 3-O-(3',3'-dimethylsuccinyl) betulinic acid (DSB), a previously described maturation inhibitor. Conversely, a single amino substitution in SP1 (SP1A1V), which was previously associated with DSB in vitro resistance, was sufficient to confer resistance to DSB and PF-46396. Further, the CAI201V substitution restored CA/SP1 processing in HIV-1-infected cells treated with PF-46396 or DSB. Our results demonstrate that PF-46396 acts through a mechanism that is similar to DSB to inhibit the maturation of HIV-1 virions. To our knowledge, PF-46396 represents the first small-molecule HIV-1 maturation inhibitor that is distinct in chemical class from betulinic acid-derived maturation inhibitors (e.g., DSB), demonstrating that molecules of diverse chemical classes can inhibit this mechanism.
|
Antiviral activity against wild type HIV1 NL4-3 infected in human MT4 cells by MTT assay
|
Human immunodeficiency virus 1
|
45.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Novel protease inhibitors (PIs) containing macrocyclic components and 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane that are potent against multi-PI-resistant HIV-1 variants in vitro.
Year : 2010
Volume : 54
Issue : 8
First Page : 3460
Last Page : 3470
Authors : Tojo Y, Koh Y, Amano M, Aoki M, Das D, Kulkarni S, Anderson DD, Ghosh AK, Mitsuya H.
Abstract : Natural products with macrocyclic structural features often display intriguing biological properties. Molecular design incorporating macrocycles may lead to molecules with unique protein-ligand interactions. We generated novel human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) containing a macrocycle and bis-tetrahydrofuranylurethane. Four such compounds exerted potent activity against HIV-1LAI and had 50% effective concentrations (EC50s) of as low as 0.002 microM with minimal cytotoxicity. GRL-216 and GRL-286 blocked the replication of HIV-1NL4-3 variants selected by up to 5 microM saquinavir, ritonavir, nelfinavir, lopinavir, or atazanavir; they had EC50s of 0.020 to 0.046 microM and potent activities against six multi-PI-resistant clinical HIV-1 (HIVmPIr) variants with EC50s of 0.027 to 0.089 microM. GRL-216 and -286 also blocked HIV-1 protease dimerization as efficiently as darunavir. When HIV-1NL4-3 was selected by GRL-216, it replicated progressively more poorly and failed to replicate in the presence of >0.26 microM GRL-216, suggesting that the emergence of GRL-216-resistant HIV-1 variants is substantially delayed. At passage 50 with GRL-216 (the HIV isolate selected with GRL-216 at up to 0.16 microM [HIV216-0.16 microM]), HIV-1NL4-3 containing the L10I, L24I, M46L, V82I, and I84V mutations remained relatively sensitive to PIs, including darunavir, with the EC50s being 3- to 8-fold-greater than the EC50 of each drug for HIV-1NL4-3. Interestingly, HIV216-0.16 microM had 10-fold increased sensitivity to tipranavir. Analysis of the protein-ligand X-ray structures of GRL-216 revealed that the macrocycle occupied a greater volume of the binding cavity of protease and formed greater van der Waals interactions with V82 and I84 than darunavir. The present data warrant the further development of GRL-216 as a potential antiviral agent for treating individuals harboring wild-type and/or HIVmPIr.
|
Antiviral activity against HIV1 expressing protease L10I/G48V/I54V/A71V/I84V/L90M mutant infected in human MT4 cells selected at 5 uM of saquinavir by MTT assay
|
Human immunodeficiency virus 1
|
510.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Novel protease inhibitors (PIs) containing macrocyclic components and 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane that are potent against multi-PI-resistant HIV-1 variants in vitro.
Year : 2010
Volume : 54
Issue : 8
First Page : 3460
Last Page : 3470
Authors : Tojo Y, Koh Y, Amano M, Aoki M, Das D, Kulkarni S, Anderson DD, Ghosh AK, Mitsuya H.
Abstract : Natural products with macrocyclic structural features often display intriguing biological properties. Molecular design incorporating macrocycles may lead to molecules with unique protein-ligand interactions. We generated novel human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) containing a macrocycle and bis-tetrahydrofuranylurethane. Four such compounds exerted potent activity against HIV-1LAI and had 50% effective concentrations (EC50s) of as low as 0.002 microM with minimal cytotoxicity. GRL-216 and GRL-286 blocked the replication of HIV-1NL4-3 variants selected by up to 5 microM saquinavir, ritonavir, nelfinavir, lopinavir, or atazanavir; they had EC50s of 0.020 to 0.046 microM and potent activities against six multi-PI-resistant clinical HIV-1 (HIVmPIr) variants with EC50s of 0.027 to 0.089 microM. GRL-216 and -286 also blocked HIV-1 protease dimerization as efficiently as darunavir. When HIV-1NL4-3 was selected by GRL-216, it replicated progressively more poorly and failed to replicate in the presence of >0.26 microM GRL-216, suggesting that the emergence of GRL-216-resistant HIV-1 variants is substantially delayed. At passage 50 with GRL-216 (the HIV isolate selected with GRL-216 at up to 0.16 microM [HIV216-0.16 microM]), HIV-1NL4-3 containing the L10I, L24I, M46L, V82I, and I84V mutations remained relatively sensitive to PIs, including darunavir, with the EC50s being 3- to 8-fold-greater than the EC50 of each drug for HIV-1NL4-3. Interestingly, HIV216-0.16 microM had 10-fold increased sensitivity to tipranavir. Analysis of the protein-ligand X-ray structures of GRL-216 revealed that the macrocycle occupied a greater volume of the binding cavity of protease and formed greater van der Waals interactions with V82 and I84 than darunavir. The present data warrant the further development of GRL-216 as a potential antiviral agent for treating individuals harboring wild-type and/or HIVmPIr.
|
Antiviral activity against HIV1 expressing protease L10F/M46I/I50V/A71V/I84V/L90M mutant infected in human MT4 cells selected at 5 uM of amprenavir by MTT assay
|
Human immunodeficiency virus 1
|
300.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Novel protease inhibitors (PIs) containing macrocyclic components and 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane that are potent against multi-PI-resistant HIV-1 variants in vitro.
Year : 2010
Volume : 54
Issue : 8
First Page : 3460
Last Page : 3470
Authors : Tojo Y, Koh Y, Amano M, Aoki M, Das D, Kulkarni S, Anderson DD, Ghosh AK, Mitsuya H.
Abstract : Natural products with macrocyclic structural features often display intriguing biological properties. Molecular design incorporating macrocycles may lead to molecules with unique protein-ligand interactions. We generated novel human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) containing a macrocycle and bis-tetrahydrofuranylurethane. Four such compounds exerted potent activity against HIV-1LAI and had 50% effective concentrations (EC50s) of as low as 0.002 microM with minimal cytotoxicity. GRL-216 and GRL-286 blocked the replication of HIV-1NL4-3 variants selected by up to 5 microM saquinavir, ritonavir, nelfinavir, lopinavir, or atazanavir; they had EC50s of 0.020 to 0.046 microM and potent activities against six multi-PI-resistant clinical HIV-1 (HIVmPIr) variants with EC50s of 0.027 to 0.089 microM. GRL-216 and -286 also blocked HIV-1 protease dimerization as efficiently as darunavir. When HIV-1NL4-3 was selected by GRL-216, it replicated progressively more poorly and failed to replicate in the presence of >0.26 microM GRL-216, suggesting that the emergence of GRL-216-resistant HIV-1 variants is substantially delayed. At passage 50 with GRL-216 (the HIV isolate selected with GRL-216 at up to 0.16 microM [HIV216-0.16 microM]), HIV-1NL4-3 containing the L10I, L24I, M46L, V82I, and I84V mutations remained relatively sensitive to PIs, including darunavir, with the EC50s being 3- to 8-fold-greater than the EC50 of each drug for HIV-1NL4-3. Interestingly, HIV216-0.16 microM had 10-fold increased sensitivity to tipranavir. Analysis of the protein-ligand X-ray structures of GRL-216 revealed that the macrocycle occupied a greater volume of the binding cavity of protease and formed greater van der Waals interactions with V82 and I84 than darunavir. The present data warrant the further development of GRL-216 as a potential antiviral agent for treating individuals harboring wild-type and/or HIVmPIr.
|
Antiviral activity against HIV1 expressing protease L10F/M46I/I54V/V82A mutant infected in human MT4 cells selected at 5 uM of Lopinavir by MTT assay
|
Human immunodeficiency virus 1
|
320.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Novel protease inhibitors (PIs) containing macrocyclic components and 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane that are potent against multi-PI-resistant HIV-1 variants in vitro.
Year : 2010
Volume : 54
Issue : 8
First Page : 3460
Last Page : 3470
Authors : Tojo Y, Koh Y, Amano M, Aoki M, Das D, Kulkarni S, Anderson DD, Ghosh AK, Mitsuya H.
Abstract : Natural products with macrocyclic structural features often display intriguing biological properties. Molecular design incorporating macrocycles may lead to molecules with unique protein-ligand interactions. We generated novel human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) containing a macrocycle and bis-tetrahydrofuranylurethane. Four such compounds exerted potent activity against HIV-1LAI and had 50% effective concentrations (EC50s) of as low as 0.002 microM with minimal cytotoxicity. GRL-216 and GRL-286 blocked the replication of HIV-1NL4-3 variants selected by up to 5 microM saquinavir, ritonavir, nelfinavir, lopinavir, or atazanavir; they had EC50s of 0.020 to 0.046 microM and potent activities against six multi-PI-resistant clinical HIV-1 (HIVmPIr) variants with EC50s of 0.027 to 0.089 microM. GRL-216 and -286 also blocked HIV-1 protease dimerization as efficiently as darunavir. When HIV-1NL4-3 was selected by GRL-216, it replicated progressively more poorly and failed to replicate in the presence of >0.26 microM GRL-216, suggesting that the emergence of GRL-216-resistant HIV-1 variants is substantially delayed. At passage 50 with GRL-216 (the HIV isolate selected with GRL-216 at up to 0.16 microM [HIV216-0.16 microM]), HIV-1NL4-3 containing the L10I, L24I, M46L, V82I, and I84V mutations remained relatively sensitive to PIs, including darunavir, with the EC50s being 3- to 8-fold-greater than the EC50 of each drug for HIV-1NL4-3. Interestingly, HIV216-0.16 microM had 10-fold increased sensitivity to tipranavir. Analysis of the protein-ligand X-ray structures of GRL-216 revealed that the macrocycle occupied a greater volume of the binding cavity of protease and formed greater van der Waals interactions with V82 and I84 than darunavir. The present data warrant the further development of GRL-216 as a potential antiviral agent for treating individuals harboring wild-type and/or HIVmPIr.
|
Antiviral activity against HIV1 expressing protease L10I/L24I/M46I/V82I/I84V mutant infected in human MT4 cells selected after 50 passages of GRL-216 by MTT assay
|
Human immunodeficiency virus 1
|
130.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Novel protease inhibitors (PIs) containing macrocyclic components and 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane that are potent against multi-PI-resistant HIV-1 variants in vitro.
Year : 2010
Volume : 54
Issue : 8
First Page : 3460
Last Page : 3470
Authors : Tojo Y, Koh Y, Amano M, Aoki M, Das D, Kulkarni S, Anderson DD, Ghosh AK, Mitsuya H.
Abstract : Natural products with macrocyclic structural features often display intriguing biological properties. Molecular design incorporating macrocycles may lead to molecules with unique protein-ligand interactions. We generated novel human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) containing a macrocycle and bis-tetrahydrofuranylurethane. Four such compounds exerted potent activity against HIV-1LAI and had 50% effective concentrations (EC50s) of as low as 0.002 microM with minimal cytotoxicity. GRL-216 and GRL-286 blocked the replication of HIV-1NL4-3 variants selected by up to 5 microM saquinavir, ritonavir, nelfinavir, lopinavir, or atazanavir; they had EC50s of 0.020 to 0.046 microM and potent activities against six multi-PI-resistant clinical HIV-1 (HIVmPIr) variants with EC50s of 0.027 to 0.089 microM. GRL-216 and -286 also blocked HIV-1 protease dimerization as efficiently as darunavir. When HIV-1NL4-3 was selected by GRL-216, it replicated progressively more poorly and failed to replicate in the presence of >0.26 microM GRL-216, suggesting that the emergence of GRL-216-resistant HIV-1 variants is substantially delayed. At passage 50 with GRL-216 (the HIV isolate selected with GRL-216 at up to 0.16 microM [HIV216-0.16 microM]), HIV-1NL4-3 containing the L10I, L24I, M46L, V82I, and I84V mutations remained relatively sensitive to PIs, including darunavir, with the EC50s being 3- to 8-fold-greater than the EC50 of each drug for HIV-1NL4-3. Interestingly, HIV216-0.16 microM had 10-fold increased sensitivity to tipranavir. Analysis of the protein-ligand X-ray structures of GRL-216 revealed that the macrocycle occupied a greater volume of the binding cavity of protease and formed greater van der Waals interactions with V82 and I84 than darunavir. The present data warrant the further development of GRL-216 as a potential antiviral agent for treating individuals harboring wild-type and/or HIVmPIr.
|
Antiviral activity against HIV1 expressing protease L10F/M46I/T91S mutant infected in human MT4 cells selected at 1 uM of GRL-246 by MTT assay
|
Human immunodeficiency virus 1
|
290.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Novel protease inhibitors (PIs) containing macrocyclic components and 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane that are potent against multi-PI-resistant HIV-1 variants in vitro.
Year : 2010
Volume : 54
Issue : 8
First Page : 3460
Last Page : 3470
Authors : Tojo Y, Koh Y, Amano M, Aoki M, Das D, Kulkarni S, Anderson DD, Ghosh AK, Mitsuya H.
Abstract : Natural products with macrocyclic structural features often display intriguing biological properties. Molecular design incorporating macrocycles may lead to molecules with unique protein-ligand interactions. We generated novel human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) containing a macrocycle and bis-tetrahydrofuranylurethane. Four such compounds exerted potent activity against HIV-1LAI and had 50% effective concentrations (EC50s) of as low as 0.002 microM with minimal cytotoxicity. GRL-216 and GRL-286 blocked the replication of HIV-1NL4-3 variants selected by up to 5 microM saquinavir, ritonavir, nelfinavir, lopinavir, or atazanavir; they had EC50s of 0.020 to 0.046 microM and potent activities against six multi-PI-resistant clinical HIV-1 (HIVmPIr) variants with EC50s of 0.027 to 0.089 microM. GRL-216 and -286 also blocked HIV-1 protease dimerization as efficiently as darunavir. When HIV-1NL4-3 was selected by GRL-216, it replicated progressively more poorly and failed to replicate in the presence of >0.26 microM GRL-216, suggesting that the emergence of GRL-216-resistant HIV-1 variants is substantially delayed. At passage 50 with GRL-216 (the HIV isolate selected with GRL-216 at up to 0.16 microM [HIV216-0.16 microM]), HIV-1NL4-3 containing the L10I, L24I, M46L, V82I, and I84V mutations remained relatively sensitive to PIs, including darunavir, with the EC50s being 3- to 8-fold-greater than the EC50 of each drug for HIV-1NL4-3. Interestingly, HIV216-0.16 microM had 10-fold increased sensitivity to tipranavir. Analysis of the protein-ligand X-ray structures of GRL-216 revealed that the macrocycle occupied a greater volume of the binding cavity of protease and formed greater van der Waals interactions with V82 and I84 than darunavir. The present data warrant the further development of GRL-216 as a potential antiviral agent for treating individuals harboring wild-type and/or HIVmPIr.
|
Antiviral activity against HIV1 expressing protease L10F/M46L/I50V/A71Vmutant infected in human MT4 cells selected at 1 uM of GRL-286 by MTT assay
|
Human immunodeficiency virus 1
|
370.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Novel protease inhibitors (PIs) containing macrocyclic components and 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane that are potent against multi-PI-resistant HIV-1 variants in vitro.
Year : 2010
Volume : 54
Issue : 8
First Page : 3460
Last Page : 3470
Authors : Tojo Y, Koh Y, Amano M, Aoki M, Das D, Kulkarni S, Anderson DD, Ghosh AK, Mitsuya H.
Abstract : Natural products with macrocyclic structural features often display intriguing biological properties. Molecular design incorporating macrocycles may lead to molecules with unique protein-ligand interactions. We generated novel human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) containing a macrocycle and bis-tetrahydrofuranylurethane. Four such compounds exerted potent activity against HIV-1LAI and had 50% effective concentrations (EC50s) of as low as 0.002 microM with minimal cytotoxicity. GRL-216 and GRL-286 blocked the replication of HIV-1NL4-3 variants selected by up to 5 microM saquinavir, ritonavir, nelfinavir, lopinavir, or atazanavir; they had EC50s of 0.020 to 0.046 microM and potent activities against six multi-PI-resistant clinical HIV-1 (HIVmPIr) variants with EC50s of 0.027 to 0.089 microM. GRL-216 and -286 also blocked HIV-1 protease dimerization as efficiently as darunavir. When HIV-1NL4-3 was selected by GRL-216, it replicated progressively more poorly and failed to replicate in the presence of >0.26 microM GRL-216, suggesting that the emergence of GRL-216-resistant HIV-1 variants is substantially delayed. At passage 50 with GRL-216 (the HIV isolate selected with GRL-216 at up to 0.16 microM [HIV216-0.16 microM]), HIV-1NL4-3 containing the L10I, L24I, M46L, V82I, and I84V mutations remained relatively sensitive to PIs, including darunavir, with the EC50s being 3- to 8-fold-greater than the EC50 of each drug for HIV-1NL4-3. Interestingly, HIV216-0.16 microM had 10-fold increased sensitivity to tipranavir. Analysis of the protein-ligand X-ray structures of GRL-216 revealed that the macrocycle occupied a greater volume of the binding cavity of protease and formed greater van der Waals interactions with V82 and I84 than darunavir. The present data warrant the further development of GRL-216 as a potential antiviral agent for treating individuals harboring wild-type and/or HIVmPIr.
|
Antiviral activity against HIV1 expressing protease L10F/M46M,I/Q61Q mutant infected in human MT4 cells selected at 1 uM of GRL-396 by MTT assay
|
Human immunodeficiency virus 1
|
220.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Novel protease inhibitors (PIs) containing macrocyclic components and 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane that are potent against multi-PI-resistant HIV-1 variants in vitro.
Year : 2010
Volume : 54
Issue : 8
First Page : 3460
Last Page : 3470
Authors : Tojo Y, Koh Y, Amano M, Aoki M, Das D, Kulkarni S, Anderson DD, Ghosh AK, Mitsuya H.
Abstract : Natural products with macrocyclic structural features often display intriguing biological properties. Molecular design incorporating macrocycles may lead to molecules with unique protein-ligand interactions. We generated novel human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) containing a macrocycle and bis-tetrahydrofuranylurethane. Four such compounds exerted potent activity against HIV-1LAI and had 50% effective concentrations (EC50s) of as low as 0.002 microM with minimal cytotoxicity. GRL-216 and GRL-286 blocked the replication of HIV-1NL4-3 variants selected by up to 5 microM saquinavir, ritonavir, nelfinavir, lopinavir, or atazanavir; they had EC50s of 0.020 to 0.046 microM and potent activities against six multi-PI-resistant clinical HIV-1 (HIVmPIr) variants with EC50s of 0.027 to 0.089 microM. GRL-216 and -286 also blocked HIV-1 protease dimerization as efficiently as darunavir. When HIV-1NL4-3 was selected by GRL-216, it replicated progressively more poorly and failed to replicate in the presence of >0.26 microM GRL-216, suggesting that the emergence of GRL-216-resistant HIV-1 variants is substantially delayed. At passage 50 with GRL-216 (the HIV isolate selected with GRL-216 at up to 0.16 microM [HIV216-0.16 microM]), HIV-1NL4-3 containing the L10I, L24I, M46L, V82I, and I84V mutations remained relatively sensitive to PIs, including darunavir, with the EC50s being 3- to 8-fold-greater than the EC50 of each drug for HIV-1NL4-3. Interestingly, HIV216-0.16 microM had 10-fold increased sensitivity to tipranavir. Analysis of the protein-ligand X-ray structures of GRL-216 revealed that the macrocycle occupied a greater volume of the binding cavity of protease and formed greater van der Waals interactions with V82 and I84 than darunavir. The present data warrant the further development of GRL-216 as a potential antiviral agent for treating individuals harboring wild-type and/or HIVmPIr.
|
Antiviral activity against R5 tropic HIV1 Ba-L infected in human PBMC assessed as inhibition of HIN p24 antigen expression
|
Human immunodeficiency virus 1
|
12.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Spirodiketopiperazine-based CCR5 antagonist: discovery of an antiretroviral drug candidate.
Year : 2011
Volume : 21
Issue : 4
First Page : 1141
Last Page : 1145
Authors : Nishizawa R, Nishiyama T, Hisaichi K, Minamoto C, Matsunaga N, Takaoka Y, Nakai H, Jenkinson S, Kazmierski WM, Tada H, Sagawa K, Shibayama S, Fukushima D, Maeda K, Mitsuya H.
Abstract : Following the discovery that hydroxylated derivative 3 (Fig. 1) was one of the oxidative metabolites of the original lead 1, it was found that hydroxylated compound 4 possesses higher in vitro anti-HIV potency than the corresponding non-hydroxylated compound 2. Structural hybridation of 4 with the orally available analog 5 resulted in another orally-available spirodiketopiperazine CCR5 antagonist 6a that possesses more favorable pharmaceutical profile for use as a drug candidate.
|
Antiretroviral activity against Human immunodeficiency virus 1 3B infected in human MT4 cells assessed as inhibition of virus-induced cytopathic effect by MTT assay
|
Human immunodeficiency virus 1
|
28.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Preclinical evaluation of 1H-benzylindole derivatives as novel human immunodeficiency virus integrase strand transfer inhibitors.
Year : 2008
Volume : 52
Issue : 8
First Page : 2861
Last Page : 2869
Authors : Hombrouck A, Van Remoortel B, Michiels M, Noppe W, Christ F, Eneroth A, Sahlberg BL, Benkestock K, Vrang L, Johansson NG, Barreca ML, De Luca L, Ferro S, Chimirri A, Debyser Z, Witvrouw M.
Abstract : We have identified 1H-benzylindole analogues as a novel series of human immunodeficiency virus (HIV) integrase inhibitors with antiretroviral activities against different strains of HIV type 1 (HIV-1), HIV-2, and simian immunodeficiency virus strain MAC(251) [SIV(MAC(251))]. Molecular modeling and structure-activity relationship-based optimization resulted in the identification of CHI/1043 as the most potent congener. CHI/1043 inhibited the replication of HIV-1(III(B)) in MT-4 cells at a 50% effective concentration (EC(50)) of 0.60 microM, 70-fold below its cytotoxic concentration. Equal activities against HIV-1(NL4.3), HIV-2(ROD), HIV-2(EHO), and SIV(MAC(251)) were observed. CHI/1043 was equally active against virus strains resistant against inhibitors of reverse transcriptase or protease. Replication of both X4 and R5 strains in peripheral blood mononuclear cells was sensitive to the inhibitory effect of CHI/1043 (EC(50), 0.30 to 0.38 microM). CHI/1043 inhibited integrase strand transfer activity in oligonucleotide-based enzymatic assays at low micromolar concentrations. Time-of-addition experiments confirmed CHI/1043 to interfere with the viral replication cycle at the time of retroviral integration. Quantitative Alu PCR corroborated that the anti-HIV activity is based upon the inhibition of proviral DNA integration. An HIV-1 strain selected for 70 passages in the presence of CHI/1043 was evaluated genotypically and phenotypically. The mutations T66I and Q146K were present in integrase. Cross-resistance to other integrase strand transfer inhibitors, such as L-708,906, the naphthyridine analogue L-870,810, and the clinical drugs GS/9137 and MK-0518, was observed. In adsorption, distribution, metabolism, excretion, and toxicity studies, antiviral activity was strongly reduced by protein binding, and metabolization in human liver microsomes was observed. Transport studies with Caco cells suggest a low oral bioavailability.
|
Antiretroviral activity against Human immunodeficiency virus 1 NL4.3 infected in human MT4 cells assessed as inhibition of virus-induced cytopathic effect by MTT assay
|
Human immunodeficiency virus 1
|
23.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Preclinical evaluation of 1H-benzylindole derivatives as novel human immunodeficiency virus integrase strand transfer inhibitors.
Year : 2008
Volume : 52
Issue : 8
First Page : 2861
Last Page : 2869
Authors : Hombrouck A, Van Remoortel B, Michiels M, Noppe W, Christ F, Eneroth A, Sahlberg BL, Benkestock K, Vrang L, Johansson NG, Barreca ML, De Luca L, Ferro S, Chimirri A, Debyser Z, Witvrouw M.
Abstract : We have identified 1H-benzylindole analogues as a novel series of human immunodeficiency virus (HIV) integrase inhibitors with antiretroviral activities against different strains of HIV type 1 (HIV-1), HIV-2, and simian immunodeficiency virus strain MAC(251) [SIV(MAC(251))]. Molecular modeling and structure-activity relationship-based optimization resulted in the identification of CHI/1043 as the most potent congener. CHI/1043 inhibited the replication of HIV-1(III(B)) in MT-4 cells at a 50% effective concentration (EC(50)) of 0.60 microM, 70-fold below its cytotoxic concentration. Equal activities against HIV-1(NL4.3), HIV-2(ROD), HIV-2(EHO), and SIV(MAC(251)) were observed. CHI/1043 was equally active against virus strains resistant against inhibitors of reverse transcriptase or protease. Replication of both X4 and R5 strains in peripheral blood mononuclear cells was sensitive to the inhibitory effect of CHI/1043 (EC(50), 0.30 to 0.38 microM). CHI/1043 inhibited integrase strand transfer activity in oligonucleotide-based enzymatic assays at low micromolar concentrations. Time-of-addition experiments confirmed CHI/1043 to interfere with the viral replication cycle at the time of retroviral integration. Quantitative Alu PCR corroborated that the anti-HIV activity is based upon the inhibition of proviral DNA integration. An HIV-1 strain selected for 70 passages in the presence of CHI/1043 was evaluated genotypically and phenotypically. The mutations T66I and Q146K were present in integrase. Cross-resistance to other integrase strand transfer inhibitors, such as L-708,906, the naphthyridine analogue L-870,810, and the clinical drugs GS/9137 and MK-0518, was observed. In adsorption, distribution, metabolism, excretion, and toxicity studies, antiviral activity was strongly reduced by protein binding, and metabolization in human liver microsomes was observed. Transport studies with Caco cells suggest a low oral bioavailability.
|
Antiretroviral activity against Human immunodeficiency virus 2 ROD infected in human MT4 cells assessed as inhibition of virus-induced cytopathic effect by MTT assay
|
Human immunodeficiency virus type 2 (ISOLATE ROD)
|
50.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Preclinical evaluation of 1H-benzylindole derivatives as novel human immunodeficiency virus integrase strand transfer inhibitors.
Year : 2008
Volume : 52
Issue : 8
First Page : 2861
Last Page : 2869
Authors : Hombrouck A, Van Remoortel B, Michiels M, Noppe W, Christ F, Eneroth A, Sahlberg BL, Benkestock K, Vrang L, Johansson NG, Barreca ML, De Luca L, Ferro S, Chimirri A, Debyser Z, Witvrouw M.
Abstract : We have identified 1H-benzylindole analogues as a novel series of human immunodeficiency virus (HIV) integrase inhibitors with antiretroviral activities against different strains of HIV type 1 (HIV-1), HIV-2, and simian immunodeficiency virus strain MAC(251) [SIV(MAC(251))]. Molecular modeling and structure-activity relationship-based optimization resulted in the identification of CHI/1043 as the most potent congener. CHI/1043 inhibited the replication of HIV-1(III(B)) in MT-4 cells at a 50% effective concentration (EC(50)) of 0.60 microM, 70-fold below its cytotoxic concentration. Equal activities against HIV-1(NL4.3), HIV-2(ROD), HIV-2(EHO), and SIV(MAC(251)) were observed. CHI/1043 was equally active against virus strains resistant against inhibitors of reverse transcriptase or protease. Replication of both X4 and R5 strains in peripheral blood mononuclear cells was sensitive to the inhibitory effect of CHI/1043 (EC(50), 0.30 to 0.38 microM). CHI/1043 inhibited integrase strand transfer activity in oligonucleotide-based enzymatic assays at low micromolar concentrations. Time-of-addition experiments confirmed CHI/1043 to interfere with the viral replication cycle at the time of retroviral integration. Quantitative Alu PCR corroborated that the anti-HIV activity is based upon the inhibition of proviral DNA integration. An HIV-1 strain selected for 70 passages in the presence of CHI/1043 was evaluated genotypically and phenotypically. The mutations T66I and Q146K were present in integrase. Cross-resistance to other integrase strand transfer inhibitors, such as L-708,906, the naphthyridine analogue L-870,810, and the clinical drugs GS/9137 and MK-0518, was observed. In adsorption, distribution, metabolism, excretion, and toxicity studies, antiviral activity was strongly reduced by protein binding, and metabolization in human liver microsomes was observed. Transport studies with Caco cells suggest a low oral bioavailability.
|
Antiretroviral activity against Human immunodeficiency virus 2 EHO infected in human MT4 cells assessed as inhibition of virus-induced cytopathic effect by MTT assay
|
Human immunodeficiency virus 2
|
49.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Preclinical evaluation of 1H-benzylindole derivatives as novel human immunodeficiency virus integrase strand transfer inhibitors.
Year : 2008
Volume : 52
Issue : 8
First Page : 2861
Last Page : 2869
Authors : Hombrouck A, Van Remoortel B, Michiels M, Noppe W, Christ F, Eneroth A, Sahlberg BL, Benkestock K, Vrang L, Johansson NG, Barreca ML, De Luca L, Ferro S, Chimirri A, Debyser Z, Witvrouw M.
Abstract : We have identified 1H-benzylindole analogues as a novel series of human immunodeficiency virus (HIV) integrase inhibitors with antiretroviral activities against different strains of HIV type 1 (HIV-1), HIV-2, and simian immunodeficiency virus strain MAC(251) [SIV(MAC(251))]. Molecular modeling and structure-activity relationship-based optimization resulted in the identification of CHI/1043 as the most potent congener. CHI/1043 inhibited the replication of HIV-1(III(B)) in MT-4 cells at a 50% effective concentration (EC(50)) of 0.60 microM, 70-fold below its cytotoxic concentration. Equal activities against HIV-1(NL4.3), HIV-2(ROD), HIV-2(EHO), and SIV(MAC(251)) were observed. CHI/1043 was equally active against virus strains resistant against inhibitors of reverse transcriptase or protease. Replication of both X4 and R5 strains in peripheral blood mononuclear cells was sensitive to the inhibitory effect of CHI/1043 (EC(50), 0.30 to 0.38 microM). CHI/1043 inhibited integrase strand transfer activity in oligonucleotide-based enzymatic assays at low micromolar concentrations. Time-of-addition experiments confirmed CHI/1043 to interfere with the viral replication cycle at the time of retroviral integration. Quantitative Alu PCR corroborated that the anti-HIV activity is based upon the inhibition of proviral DNA integration. An HIV-1 strain selected for 70 passages in the presence of CHI/1043 was evaluated genotypically and phenotypically. The mutations T66I and Q146K were present in integrase. Cross-resistance to other integrase strand transfer inhibitors, such as L-708,906, the naphthyridine analogue L-870,810, and the clinical drugs GS/9137 and MK-0518, was observed. In adsorption, distribution, metabolism, excretion, and toxicity studies, antiviral activity was strongly reduced by protein binding, and metabolization in human liver microsomes was observed. Transport studies with Caco cells suggest a low oral bioavailability.
|
Antiretroviral activity against Simian immunodeficiency virus MAC 251 infected in human MT4 cells assessed as inhibition of virus-induced cytopathic effect by MTT assay
|
Simian immunodeficiency virus
|
50.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Preclinical evaluation of 1H-benzylindole derivatives as novel human immunodeficiency virus integrase strand transfer inhibitors.
Year : 2008
Volume : 52
Issue : 8
First Page : 2861
Last Page : 2869
Authors : Hombrouck A, Van Remoortel B, Michiels M, Noppe W, Christ F, Eneroth A, Sahlberg BL, Benkestock K, Vrang L, Johansson NG, Barreca ML, De Luca L, Ferro S, Chimirri A, Debyser Z, Witvrouw M.
Abstract : We have identified 1H-benzylindole analogues as a novel series of human immunodeficiency virus (HIV) integrase inhibitors with antiretroviral activities against different strains of HIV type 1 (HIV-1), HIV-2, and simian immunodeficiency virus strain MAC(251) [SIV(MAC(251))]. Molecular modeling and structure-activity relationship-based optimization resulted in the identification of CHI/1043 as the most potent congener. CHI/1043 inhibited the replication of HIV-1(III(B)) in MT-4 cells at a 50% effective concentration (EC(50)) of 0.60 microM, 70-fold below its cytotoxic concentration. Equal activities against HIV-1(NL4.3), HIV-2(ROD), HIV-2(EHO), and SIV(MAC(251)) were observed. CHI/1043 was equally active against virus strains resistant against inhibitors of reverse transcriptase or protease. Replication of both X4 and R5 strains in peripheral blood mononuclear cells was sensitive to the inhibitory effect of CHI/1043 (EC(50), 0.30 to 0.38 microM). CHI/1043 inhibited integrase strand transfer activity in oligonucleotide-based enzymatic assays at low micromolar concentrations. Time-of-addition experiments confirmed CHI/1043 to interfere with the viral replication cycle at the time of retroviral integration. Quantitative Alu PCR corroborated that the anti-HIV activity is based upon the inhibition of proviral DNA integration. An HIV-1 strain selected for 70 passages in the presence of CHI/1043 was evaluated genotypically and phenotypically. The mutations T66I and Q146K were present in integrase. Cross-resistance to other integrase strand transfer inhibitors, such as L-708,906, the naphthyridine analogue L-870,810, and the clinical drugs GS/9137 and MK-0518, was observed. In adsorption, distribution, metabolism, excretion, and toxicity studies, antiviral activity was strongly reduced by protein binding, and metabolization in human liver microsomes was observed. Transport studies with Caco cells suggest a low oral bioavailability.
|
Antiviral activity against Reverse transcriptase inhibitor-resistant Human immunodeficiency virus 1 infected in human MT4 cells assessed as inhibition of virus-induced cytopathic effect by MTT assay
|
Human immunodeficiency virus 1
|
29.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Preclinical evaluation of 1H-benzylindole derivatives as novel human immunodeficiency virus integrase strand transfer inhibitors.
Year : 2008
Volume : 52
Issue : 8
First Page : 2861
Last Page : 2869
Authors : Hombrouck A, Van Remoortel B, Michiels M, Noppe W, Christ F, Eneroth A, Sahlberg BL, Benkestock K, Vrang L, Johansson NG, Barreca ML, De Luca L, Ferro S, Chimirri A, Debyser Z, Witvrouw M.
Abstract : We have identified 1H-benzylindole analogues as a novel series of human immunodeficiency virus (HIV) integrase inhibitors with antiretroviral activities against different strains of HIV type 1 (HIV-1), HIV-2, and simian immunodeficiency virus strain MAC(251) [SIV(MAC(251))]. Molecular modeling and structure-activity relationship-based optimization resulted in the identification of CHI/1043 as the most potent congener. CHI/1043 inhibited the replication of HIV-1(III(B)) in MT-4 cells at a 50% effective concentration (EC(50)) of 0.60 microM, 70-fold below its cytotoxic concentration. Equal activities against HIV-1(NL4.3), HIV-2(ROD), HIV-2(EHO), and SIV(MAC(251)) were observed. CHI/1043 was equally active against virus strains resistant against inhibitors of reverse transcriptase or protease. Replication of both X4 and R5 strains in peripheral blood mononuclear cells was sensitive to the inhibitory effect of CHI/1043 (EC(50), 0.30 to 0.38 microM). CHI/1043 inhibited integrase strand transfer activity in oligonucleotide-based enzymatic assays at low micromolar concentrations. Time-of-addition experiments confirmed CHI/1043 to interfere with the viral replication cycle at the time of retroviral integration. Quantitative Alu PCR corroborated that the anti-HIV activity is based upon the inhibition of proviral DNA integration. An HIV-1 strain selected for 70 passages in the presence of CHI/1043 was evaluated genotypically and phenotypically. The mutations T66I and Q146K were present in integrase. Cross-resistance to other integrase strand transfer inhibitors, such as L-708,906, the naphthyridine analogue L-870,810, and the clinical drugs GS/9137 and MK-0518, was observed. In adsorption, distribution, metabolism, excretion, and toxicity studies, antiviral activity was strongly reduced by protein binding, and metabolization in human liver microsomes was observed. Transport studies with Caco cells suggest a low oral bioavailability.
|
Antiviral activity against non nucleoside reverse transcriptase inhibitor-resistant Human immunodeficiency virus 1 infected in human MT4 cells assessed as inhibition of virus-induced cytopathic effect by MTT assay
|
Human immunodeficiency virus 1
|
35.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Preclinical evaluation of 1H-benzylindole derivatives as novel human immunodeficiency virus integrase strand transfer inhibitors.
Year : 2008
Volume : 52
Issue : 8
First Page : 2861
Last Page : 2869
Authors : Hombrouck A, Van Remoortel B, Michiels M, Noppe W, Christ F, Eneroth A, Sahlberg BL, Benkestock K, Vrang L, Johansson NG, Barreca ML, De Luca L, Ferro S, Chimirri A, Debyser Z, Witvrouw M.
Abstract : We have identified 1H-benzylindole analogues as a novel series of human immunodeficiency virus (HIV) integrase inhibitors with antiretroviral activities against different strains of HIV type 1 (HIV-1), HIV-2, and simian immunodeficiency virus strain MAC(251) [SIV(MAC(251))]. Molecular modeling and structure-activity relationship-based optimization resulted in the identification of CHI/1043 as the most potent congener. CHI/1043 inhibited the replication of HIV-1(III(B)) in MT-4 cells at a 50% effective concentration (EC(50)) of 0.60 microM, 70-fold below its cytotoxic concentration. Equal activities against HIV-1(NL4.3), HIV-2(ROD), HIV-2(EHO), and SIV(MAC(251)) were observed. CHI/1043 was equally active against virus strains resistant against inhibitors of reverse transcriptase or protease. Replication of both X4 and R5 strains in peripheral blood mononuclear cells was sensitive to the inhibitory effect of CHI/1043 (EC(50), 0.30 to 0.38 microM). CHI/1043 inhibited integrase strand transfer activity in oligonucleotide-based enzymatic assays at low micromolar concentrations. Time-of-addition experiments confirmed CHI/1043 to interfere with the viral replication cycle at the time of retroviral integration. Quantitative Alu PCR corroborated that the anti-HIV activity is based upon the inhibition of proviral DNA integration. An HIV-1 strain selected for 70 passages in the presence of CHI/1043 was evaluated genotypically and phenotypically. The mutations T66I and Q146K were present in integrase. Cross-resistance to other integrase strand transfer inhibitors, such as L-708,906, the naphthyridine analogue L-870,810, and the clinical drugs GS/9137 and MK-0518, was observed. In adsorption, distribution, metabolism, excretion, and toxicity studies, antiviral activity was strongly reduced by protein binding, and metabolization in human liver microsomes was observed. Transport studies with Caco cells suggest a low oral bioavailability.
|
Antiviral activity against Protease inhibitor-resistant Human immunodeficiency virus 1 infected in human MT4 cells assessed as inhibition of virus-induced cytopathic effect by MTT assay
|
Human immunodeficiency virus 1
|
170.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Preclinical evaluation of 1H-benzylindole derivatives as novel human immunodeficiency virus integrase strand transfer inhibitors.
Year : 2008
Volume : 52
Issue : 8
First Page : 2861
Last Page : 2869
Authors : Hombrouck A, Van Remoortel B, Michiels M, Noppe W, Christ F, Eneroth A, Sahlberg BL, Benkestock K, Vrang L, Johansson NG, Barreca ML, De Luca L, Ferro S, Chimirri A, Debyser Z, Witvrouw M.
Abstract : We have identified 1H-benzylindole analogues as a novel series of human immunodeficiency virus (HIV) integrase inhibitors with antiretroviral activities against different strains of HIV type 1 (HIV-1), HIV-2, and simian immunodeficiency virus strain MAC(251) [SIV(MAC(251))]. Molecular modeling and structure-activity relationship-based optimization resulted in the identification of CHI/1043 as the most potent congener. CHI/1043 inhibited the replication of HIV-1(III(B)) in MT-4 cells at a 50% effective concentration (EC(50)) of 0.60 microM, 70-fold below its cytotoxic concentration. Equal activities against HIV-1(NL4.3), HIV-2(ROD), HIV-2(EHO), and SIV(MAC(251)) were observed. CHI/1043 was equally active against virus strains resistant against inhibitors of reverse transcriptase or protease. Replication of both X4 and R5 strains in peripheral blood mononuclear cells was sensitive to the inhibitory effect of CHI/1043 (EC(50), 0.30 to 0.38 microM). CHI/1043 inhibited integrase strand transfer activity in oligonucleotide-based enzymatic assays at low micromolar concentrations. Time-of-addition experiments confirmed CHI/1043 to interfere with the viral replication cycle at the time of retroviral integration. Quantitative Alu PCR corroborated that the anti-HIV activity is based upon the inhibition of proviral DNA integration. An HIV-1 strain selected for 70 passages in the presence of CHI/1043 was evaluated genotypically and phenotypically. The mutations T66I and Q146K were present in integrase. Cross-resistance to other integrase strand transfer inhibitors, such as L-708,906, the naphthyridine analogue L-870,810, and the clinical drugs GS/9137 and MK-0518, was observed. In adsorption, distribution, metabolism, excretion, and toxicity studies, antiviral activity was strongly reduced by protein binding, and metabolization in human liver microsomes was observed. Transport studies with Caco cells suggest a low oral bioavailability.
|
Mechanism based inhibition of human cytochrome P450 3A4 measured by testosterone hydroxylation
|
Homo sapiens
|
480.0
nM
|
|
Journal : Curr. Drug Metab.
Title : Cytochrome p450 enzymes mechanism based inhibitors: common sub-structures and reactivity.
Year : 2005
Volume : 6
Issue : 1
First Page : 413
Last Page : 454
Authors : Fontana E, Dansette PM, Poli SM.
Abstract : The inhibition of human cytochrome P450s (CYPs) is one of the most common mechanisms which can lead to drug-drug interactions. The inhibition of CYPs can be reversible (competitive or non-competitive) or irreversible. Irreversible inhibition usually derives from activation of a drug by CYPs into a reactive metabolite, which tightly binds to the enzyme active site, leading to a long lasting inactivation. This process is called "mechanism based inhibition" or "suicide inhibition". The irreversible inactivation usually implies the formation of a covalent bond between the metabolite and the enzyme, which can lead to hapten formation and can in some cases trigger an autoimmune-response. For these reasons it is of utmost importance to study the mechanism of the CYP inhibition of new potential drugs as early as possible during the drug discovery process. The literature on CYPs is vast and covers numerous aspects of their biology and biochemistry, however to our knowledge there is no general and systematic review focusing on mechanism-based inhibitors; we have reviewed the literature and compiled all the available data on chemical entities, which are known to be CYP suicide inhibitors. Each compound is reported together with its chemical structure, the CYP isoform and the parameters describing the inactivation. Literature references are reported together with their PMID (PubMed ID number) to allow a fast retrieval of the papers. This review offers a quick reference to help predict liabilities of new chemical entities without carrying out extensive in vitro work, and will hopefully help in designing safer drugs.
|
Mechanism based inhibition of human cytochrome P450 3A5 measured by testosterone hydroxylation
|
Homo sapiens
|
570.0
nM
|
|
Journal : Curr. Drug Metab.
Title : Cytochrome p450 enzymes mechanism based inhibitors: common sub-structures and reactivity.
Year : 2005
Volume : 6
Issue : 1
First Page : 413
Last Page : 454
Authors : Fontana E, Dansette PM, Poli SM.
Abstract : The inhibition of human cytochrome P450s (CYPs) is one of the most common mechanisms which can lead to drug-drug interactions. The inhibition of CYPs can be reversible (competitive or non-competitive) or irreversible. Irreversible inhibition usually derives from activation of a drug by CYPs into a reactive metabolite, which tightly binds to the enzyme active site, leading to a long lasting inactivation. This process is called "mechanism based inhibition" or "suicide inhibition". The irreversible inactivation usually implies the formation of a covalent bond between the metabolite and the enzyme, which can lead to hapten formation and can in some cases trigger an autoimmune-response. For these reasons it is of utmost importance to study the mechanism of the CYP inhibition of new potential drugs as early as possible during the drug discovery process. The literature on CYPs is vast and covers numerous aspects of their biology and biochemistry, however to our knowledge there is no general and systematic review focusing on mechanism-based inhibitors; we have reviewed the literature and compiled all the available data on chemical entities, which are known to be CYP suicide inhibitors. Each compound is reported together with its chemical structure, the CYP isoform and the parameters describing the inactivation. Literature references are reported together with their PMID (PubMed ID number) to allow a fast retrieval of the papers. This review offers a quick reference to help predict liabilities of new chemical entities without carrying out extensive in vitro work, and will hopefully help in designing safer drugs.
|
Antiviral activity against R5 tropic HIV1 Ba-L infected PBMC assessed as inhibition of viral p24 antigen expression
|
Human immunodeficiency virus 1
|
12.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of 4-[4-({(3R)-1-butyl-3-[(R)-cyclohexyl(hydroxy)methyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undec-9-yl}methyl)phenoxy]benzoic acid hydrochloride: a highly potent orally available CCR5 selective antagonist.
Year : 2011
Volume : 19
Issue : 13
First Page : 4028
Last Page : 4042
Authors : Nishizawa R, Nishiyama T, Hisaichi K, Minamoto C, Murota M, Takaoka Y, Nakai H, Tada H, Sagawa K, Shibayama S, Fukushima D, Maeda K, Mitsuya H.
Abstract : Based on the original spirodiketopiperazine design framework, further optimization of an orally available CCR5 antagonist was undertaken. Structural hybridization of the hydroxylated analog 4 derived from one of the oxidative metabolites and the new orally available non-hydroxylated benzoic acid analog 5 resulted in another potent orally available CCR5 antagonist 6a as a clinical candidate. Full details of a structure-activity relationship (SAR) study and ADME properties are presented.
|
Inhibition of wild type HIV-1 protease assessed as hydrolysis of fluorogenic substrate Abz-Thr-Ile-Nle-Phe(NO2)-Gln-Arg after 10 mins by fluorescence assay
|
Human immunodeficiency virus 1
|
9.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of novel small non-peptidic HIV-1 PIs: the benzothiophene ring as an effective moiety.
Year : 2012
Volume : 22
Issue : 8
First Page : 2948
Last Page : 2950
Authors : Chiummiento L, Funicello M, Lupattelli P, Tramutola F, Berti F, Marino-Merlo F.
Abstract : Synthesis and biological evaluation of a new series of potential HIV-1 protease inhibitors incorporating different heterocycles are described. The variation of heteroatom in such molecules has displayed totally different biological activities and a benzothiophene containing inhibitor has shown high potency against wild type HIV-1 protease with IC(50)=60 nM, thanks to the lower desolvation penalty to be payed by such hydrophobic moiety.
|
Binding affinity to Human immunodeficiency virus 1 protease by SPR biosensor interaction analysis at pH 7.4
|
Human immunodeficiency virus 1
|
3.4
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Experimental and 'in silico' analysis of the effect of pH on HIV-1 protease inhibitor affinity: implications for the charge state of the protein ionogenic groups.
Year : 2012
Volume : 20
Issue : 15
First Page : 4838
Last Page : 4847
Authors : Domínguez JL, Gossas T, Carmen Villaverde M, Helena Danielson U, Sussman F.
Abstract : The pH dependence of the HIV-1 protease inhibitor affinity was studied by determining the interaction kinetics of a series of inhibitors at three pH values by surface plasmon resonance (SPR) biosensor analysis. The results were rationalized by molecular mechanics based protocols that have as a starting point the structures of the HIV-1 protease inhibitor complexes differing in the protonation states as predicted by our calculations. The SPR experiments indicate a variety of binding affinity pH dependencies which are rather well reproduced by our simulations. Moreover, our calculations are able to pinpoint the possible changes in the charged state of the protein binding site and of the inhibitor that underlie the observed effects of the pH on binding affinity. The combination of SPR and molecular mechanics calculations has afforded novel insights into the pH dependence of inhibitor interactions with their target. This work raises the possibility of designing inhibitors with different pH binding affinity profiles to the ones described here.
|
Binding affinity to Human immunodeficiency virus 1 protease by SPR biosensor interaction analysis at pH 5.1
|
Human immunodeficiency virus 1
|
2.99
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Experimental and 'in silico' analysis of the effect of pH on HIV-1 protease inhibitor affinity: implications for the charge state of the protein ionogenic groups.
Year : 2012
Volume : 20
Issue : 15
First Page : 4838
Last Page : 4847
Authors : Domínguez JL, Gossas T, Carmen Villaverde M, Helena Danielson U, Sussman F.
Abstract : The pH dependence of the HIV-1 protease inhibitor affinity was studied by determining the interaction kinetics of a series of inhibitors at three pH values by surface plasmon resonance (SPR) biosensor analysis. The results were rationalized by molecular mechanics based protocols that have as a starting point the structures of the HIV-1 protease inhibitor complexes differing in the protonation states as predicted by our calculations. The SPR experiments indicate a variety of binding affinity pH dependencies which are rather well reproduced by our simulations. Moreover, our calculations are able to pinpoint the possible changes in the charged state of the protein binding site and of the inhibitor that underlie the observed effects of the pH on binding affinity. The combination of SPR and molecular mechanics calculations has afforded novel insights into the pH dependence of inhibitor interactions with their target. This work raises the possibility of designing inhibitors with different pH binding affinity profiles to the ones described here.
|
Binding affinity to Human immunodeficiency virus 1 protease by SPR biosensor interaction analysis at pH 4.1
|
Human immunodeficiency virus 1
|
37.6
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Experimental and 'in silico' analysis of the effect of pH on HIV-1 protease inhibitor affinity: implications for the charge state of the protein ionogenic groups.
Year : 2012
Volume : 20
Issue : 15
First Page : 4838
Last Page : 4847
Authors : Domínguez JL, Gossas T, Carmen Villaverde M, Helena Danielson U, Sussman F.
Abstract : The pH dependence of the HIV-1 protease inhibitor affinity was studied by determining the interaction kinetics of a series of inhibitors at three pH values by surface plasmon resonance (SPR) biosensor analysis. The results were rationalized by molecular mechanics based protocols that have as a starting point the structures of the HIV-1 protease inhibitor complexes differing in the protonation states as predicted by our calculations. The SPR experiments indicate a variety of binding affinity pH dependencies which are rather well reproduced by our simulations. Moreover, our calculations are able to pinpoint the possible changes in the charged state of the protein binding site and of the inhibitor that underlie the observed effects of the pH on binding affinity. The combination of SPR and molecular mechanics calculations has afforded novel insights into the pH dependence of inhibitor interactions with their target. This work raises the possibility of designing inhibitors with different pH binding affinity profiles to the ones described here.
|
Inhibition of human liver OATP1B1 expressed in HEK293 Flp-In cells assessed as reduction in E17-betaG uptake at 20 uM by scintillation counting
|
Homo sapiens
|
71.3
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP1B3 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E17-betaG uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
59.3
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP2B1 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E3S uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
50.0
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of ACE (unknown origin) assessed as 3-Hydroxybutyril-glycil-glycil-glycine conversion to 3-hydroxybutyric acid at 500 uM after 60 mins by WST assay relative to control
|
Homo sapiens
|
48.0
%
|
|
Journal : J. Med. Chem.
Title : Experimental confirmation of new drug-target interactions predicted by Drug Profile Matching.
Year : 2013
Volume : 56
Issue : 21
First Page : 8377
Last Page : 8388
Authors : Végner L, Peragovics Á, Tombor L, Jelinek B, Czobor P, Bender A, Simon Z, Málnási-Csizmadia A.
Abstract : We recently introduced Drug Profile Matching (DPM), a novel affinity fingerprinting-based in silico drug repositioning approach. DPM is able to quantitatively predict the complete effect profiles of compounds via probability scores. In the present work, in order to investigate the predictive power of DPM, three effect categories, namely, angiotensin-converting enzyme inhibitor, cyclooxygenase inhibitor, and dopamine agent, were selected and predictions were verified by literature analysis as well as experimentally. A total of 72% of the newly predicted and tested dopaminergic compounds were confirmed by tests on D1 and D2 expressing cell cultures. 33% and 23% of the ACE and COX inhibitory predictions were confirmed by in vitro tests, respectively. Dose-dependent inhibition curves were measured for seven drugs, and their inhibitory constants (Ki) were determined. Our study overall demonstrates that DPM is an effective approach to reveal novel drug-target pairs that may result in repositioning these drugs.
|
Inhibition of HIV1 protease using fluorogenic hexapeptide substrate (2-aminobenzoyl)Thr-Ile-Nle-(p-nitro)Phe-Gln-Arg by fluorimeter
|
Human immunodeficiency virus 1
|
0.732
nM
|
|
Journal : MedChemComm
Title : Discovery of GS-8374, a potent human immunodeficiency virus type 1 protease inhibitor with a superior resistance profile
Year : 2011
Volume : 2
Issue : 11
First Page : 1093
Last Page : 1098
Authors : He G, Yang Z, Williams M, Callebaut C, Cihlar T, Murray BP, Yang C, Mitchell ML, Liu H, Wang J, Arimilli M, Eisenberg E, Stray KM, Tsai LK, Hatada M, Chen X, Chen JM, Wang Y, Lee MS, Strickley RG, Iwata Q, Zheng X, Kim CU, Swaminathan S, Desai MC, Lee WA, Xu L
|
Antiviral activity against wild type HIV1 3B infected in human MT2 cells assessed as virus-induced cytopathic effect after 5 days by XTT assay
|
Human immunodeficiency virus 1
|
4.9
nM
|
|
Journal : MedChemComm
Title : Discovery of GS-8374, a potent human immunodeficiency virus type 1 protease inhibitor with a superior resistance profile
Year : 2011
Volume : 2
Issue : 11
First Page : 1093
Last Page : 1098
Authors : He G, Yang Z, Williams M, Callebaut C, Cihlar T, Murray BP, Yang C, Mitchell ML, Liu H, Wang J, Arimilli M, Eisenberg E, Stray KM, Tsai LK, Hatada M, Chen X, Chen JM, Wang Y, Lee MS, Strickley RG, Iwata Q, Zheng X, Kim CU, Swaminathan S, Desai MC, Lee WA, Xu L
|
Induction of mitochondrial dysfunction in Sprague-Dawley rat liver mitochondria assessed as inhibition of mitochondrial respiration per mg mitochondrial protein measured for 20 mins by A65N-1 oxygen probe based fluorescence assay
|
Rattus norvegicus
|
100.0
nM
|
|
Journal : Hepatology
Title : Human drug-induced liver injury severity is highly associated with dual inhibition of liver mitochondrial function and bile salt export pump.
Year : 2014
Volume : 60
Issue : 3
First Page : 1015
Last Page : 1022
Authors : Aleo MD, Luo Y, Swiss R, Bonin PD, Potter DM, Will Y.
Abstract : Drug-induced liver injury (DILI) accounts for 20-40% of all instances of clinical hepatic failure and is a common reason for withdrawal of an approved drug or discontinuation of a potentially new drug from clinical/nonclinical development. Numerous individual risk factors contribute to the susceptibility to human DILI and its severity that are either compound- and/or patient-specific. Compound-specific primary mechanisms linked to DILI include: cytotoxicity, reactive metabolite formation, inhibition of bile salt export pump (BSEP), and mitochondrial dysfunction. Since BSEP is an energy-dependent protein responsible for the efflux of bile acids from hepatocytes, it was hypothesized that humans exposed to drugs that impair both mitochondrial energetics and BSEP functional activity are more sensitive to more severe manifestations of DILI than drugs that only have a single liability factor. As annotated in the United States National Center for Toxicological Research Liver Toxicity Knowledge Base (NCTR-LTKB), the inhibitory properties of 24 Most-DILI-, 28 Less-DILI-, and 20 No-DILI-concern drugs were investigated. Drug potency for inhibiting BSEP or mitochondrial activity was generally correlated across human DILI concern categories. However, drugs with dual potency as mitochondrial and BSEP inhibitors were highly associated with more severe human DILI, more restrictive product safety labeling related to liver injury, and appear more sensitive to the drug exposure (Cmax) where more restrictive labeling occurs.These data affirm that severe manifestations of human DILI are multifactorial, highly associated with combinations of drug potency specifically related to known mechanisms of DILI (like mitochondrial and BSEP inhibition), and, along with patient-specific factors, lead to differences in the severity and exposure thresholds associated with clinical DILI.
