|
Inhibition of recombinant HIV1 integrase strand transfer activity
|
Human immunodeficiency virus 1
|
7.2
nM
|
|
Journal : J. Med. Chem.
Title : Novel HIV-1 integrase inhibitors derived from quinolone antibiotics.
Year : 2006
Volume : 49
Issue : 5
First Page : 1506
Last Page : 1508
Authors : Sato M, Motomura T, Aramaki H, Matsuda T, Yamashita M, Ito Y, Kawakami H, Matsuzaki Y, Watanabe W, Yamataka K, Ikeda S, Kodama E, Matsuoka M, Shinkai H.
Abstract : The viral enzyme integrase is essential for the replication of human immunodeficiency virus type 1 (HIV-1) and represents a remaining target for antiretroviral drugs. Here, we describe the modification of a quinolone antibiotic to produce the novel integrase inhibitor JTK-303 (GS 9137) that blocks strand transfer by the viral enzyme. It shares the core structure of quinolone antibiotics, exhibits an IC50 of 7.2 nM in the strand transfer assay, and shows an EC50 of 0.9 nM in an acute HIV-1 infection assay.
|
Antiviral activity against HIV1 3b in human MT4 cells
|
None
|
0.9
nM
|
|
Journal : J. Med. Chem.
Title : Novel HIV-1 integrase inhibitors derived from quinolone antibiotics.
Year : 2006
Volume : 49
Issue : 5
First Page : 1506
Last Page : 1508
Authors : Sato M, Motomura T, Aramaki H, Matsuda T, Yamashita M, Ito Y, Kawakami H, Matsuzaki Y, Watanabe W, Yamataka K, Ikeda S, Kodama E, Matsuoka M, Shinkai H.
Abstract : The viral enzyme integrase is essential for the replication of human immunodeficiency virus type 1 (HIV-1) and represents a remaining target for antiretroviral drugs. Here, we describe the modification of a quinolone antibiotic to produce the novel integrase inhibitor JTK-303 (GS 9137) that blocks strand transfer by the viral enzyme. It shares the core structure of quinolone antibiotics, exhibits an IC50 of 7.2 nM in the strand transfer assay, and shows an EC50 of 0.9 nM in an acute HIV-1 infection assay.
|
Antiviral activity against human immunodeficiency virus 1 in cell culture
|
Human immunodeficiency virus 1
|
0.9
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Development of integrase inhibitors for treatment of AIDS: an overview.
Year : 2007
Volume : 42
Issue : 9
First Page : 1159
Last Page : 1168
Authors : Dubey S, Satyanarayana YD, Lavania H.
Abstract : HIV-1 integrase (IN) is an essential enzyme for retroviral replication. It is involved in the integration of HIV DNA into host chromosomal DNA. The unique properties of IN makes it an ideal target for drug design. First, there appears to have no functional equivalent in human cells and the reactions catalyzed by IN are unique. Second, IN is absolutely required for viral replication and mutations in a number of key residues block the viral replication. Third, IN has been validated as a legitimate target and the results from the molecules like S-1,360, JKT-303 which are under phase II/III clinical trials suggest synergistic effect with reverse transcriptase (RT) and protease (PR) inhibitors. During the past 10 years a plethora of inhibitors have been identified and some were shown to be selective against IN and block viral replication. The classes under which inhibitors of integrase can be classified are catechol-containing hydroxylated aromatics, diketoacid-containing aromatics, quninolines and others (non-catechol containing). In the present article we review all the recent small molecules reported to inhibit recombinant HIV-1 IN under these heads. It seems likely that the efficient use of HIV IN as target for rational design can give potent anti-HIV agents, which can be used alone or in combination regimens with other classes of anti-HIV drugs.
|
Inhibition of HIV1 integrase strand transfer activity
|
Human immunodeficiency virus 1
|
7.2
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Development of integrase inhibitors for treatment of AIDS: an overview.
Year : 2007
Volume : 42
Issue : 9
First Page : 1159
Last Page : 1168
Authors : Dubey S, Satyanarayana YD, Lavania H.
Abstract : HIV-1 integrase (IN) is an essential enzyme for retroviral replication. It is involved in the integration of HIV DNA into host chromosomal DNA. The unique properties of IN makes it an ideal target for drug design. First, there appears to have no functional equivalent in human cells and the reactions catalyzed by IN are unique. Second, IN is absolutely required for viral replication and mutations in a number of key residues block the viral replication. Third, IN has been validated as a legitimate target and the results from the molecules like S-1,360, JKT-303 which are under phase II/III clinical trials suggest synergistic effect with reverse transcriptase (RT) and protease (PR) inhibitors. During the past 10 years a plethora of inhibitors have been identified and some were shown to be selective against IN and block viral replication. The classes under which inhibitors of integrase can be classified are catechol-containing hydroxylated aromatics, diketoacid-containing aromatics, quninolines and others (non-catechol containing). In the present article we review all the recent small molecules reported to inhibit recombinant HIV-1 IN under these heads. It seems likely that the efficient use of HIV IN as target for rational design can give potent anti-HIV agents, which can be used alone or in combination regimens with other classes of anti-HIV drugs.
|
Inhibition of HIV1 integrase
|
Human immunodeficiency virus 1
|
4.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A refined pharmacophore model for HIV-1 integrase inhibitors: Optimization of potency in the 1H-benzylindole series.
Year : 2008
Volume : 18
Issue : 9
First Page : 2891
Last Page : 2895
Authors : De Luca L, Barreca ML, Ferro S, Iraci N, Michiels M, Christ F, Debyser Z, Witvrouw M, Chimirri A.
Abstract : We report herein the development of a new three-dimensional pharmacophore model for HIV-1 integrase inhibitors which led to the discovery of some 4-[1-(4-fluorobenzyl)-1H-indol-3-yl]-2-hydroxy-4-oxobut-2-enoic acids that are able to specifically inhibit the strand transfer step of integration at nanomolar concentration. The synthesis of the new designed molecules is also described.
|
Inhibition of HIV1 integrase strand transfer activity
|
Human immunodeficiency virus 1
|
15.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A refined pharmacophore model for HIV-1 integrase inhibitors: Optimization of potency in the 1H-benzylindole series.
Year : 2008
Volume : 18
Issue : 9
First Page : 2891
Last Page : 2895
Authors : De Luca L, Barreca ML, Ferro S, Iraci N, Michiels M, Christ F, Debyser Z, Witvrouw M, Chimirri A.
Abstract : We report herein the development of a new three-dimensional pharmacophore model for HIV-1 integrase inhibitors which led to the discovery of some 4-[1-(4-fluorobenzyl)-1H-indol-3-yl]-2-hydroxy-4-oxobut-2-enoic acids that are able to specifically inhibit the strand transfer step of integration at nanomolar concentration. The synthesis of the new designed molecules is also described.
|
Antiviral activity against HIV1 3B assessed as inhibition of viral-induced cytopathic effect in human MT4 cells
|
Human immunodeficiency virus 1
|
0.8
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A refined pharmacophore model for HIV-1 integrase inhibitors: Optimization of potency in the 1H-benzylindole series.
Year : 2008
Volume : 18
Issue : 9
First Page : 2891
Last Page : 2895
Authors : De Luca L, Barreca ML, Ferro S, Iraci N, Michiels M, Christ F, Debyser Z, Witvrouw M, Chimirri A.
Abstract : We report herein the development of a new three-dimensional pharmacophore model for HIV-1 integrase inhibitors which led to the discovery of some 4-[1-(4-fluorobenzyl)-1H-indol-3-yl]-2-hydroxy-4-oxobut-2-enoic acids that are able to specifically inhibit the strand transfer step of integration at nanomolar concentration. The synthesis of the new designed molecules is also described.
|
Inhibition of HIV1 integrase by overall integration assay
|
Human immunodeficiency virus 1
|
2.0
nM
|
|
Journal : J. Med. Chem.
Title : Investigations on the 4-quinolone-3-carboxylic acid motif. 1. Synthesis and structure-activity relationship of a class of human immunodeficiency virus type 1 integrase inhibitors.
Year : 2008
Volume : 51
Issue : 16
First Page : 5125
Last Page : 5129
Authors : Pasquini S, Mugnaini C, Tintori C, Botta M, Trejos A, Arvela RK, Larhed M, Witvrouw M, Michiels M, Christ F, Debyser Z, Corelli F.
Abstract : A set of 4-quinolone-3-carboxylic acids bearing different substituents on the condensed benzene ring was designed and synthesized as potential HIV-1 integrase inhibitors structurally related to elvitegravir. Some of the new compounds proved to be able to inhibit the strand transfer step of the virus integration process in the micromolar range. Docking studies and quantum mechanics calculations were used to rationalize these data.
|
Inhibition of HIV1 integrase 3'-processing activity
|
Human immunodeficiency virus 1
|
50.0
nM
|
|
Journal : J. Med. Chem.
Title : Investigations on the 4-quinolone-3-carboxylic acid motif. 1. Synthesis and structure-activity relationship of a class of human immunodeficiency virus type 1 integrase inhibitors.
Year : 2008
Volume : 51
Issue : 16
First Page : 5125
Last Page : 5129
Authors : Pasquini S, Mugnaini C, Tintori C, Botta M, Trejos A, Arvela RK, Larhed M, Witvrouw M, Michiels M, Christ F, Debyser Z, Corelli F.
Abstract : A set of 4-quinolone-3-carboxylic acids bearing different substituents on the condensed benzene ring was designed and synthesized as potential HIV-1 integrase inhibitors structurally related to elvitegravir. Some of the new compounds proved to be able to inhibit the strand transfer step of the virus integration process in the micromolar range. Docking studies and quantum mechanics calculations were used to rationalize these data.
|
Inhibition of HIV1 integrase DNA strand transfer activity
|
Human immunodeficiency virus 1
|
7.0
nM
|
|
Journal : J. Med. Chem.
Title : Investigations on the 4-quinolone-3-carboxylic acid motif. 1. Synthesis and structure-activity relationship of a class of human immunodeficiency virus type 1 integrase inhibitors.
Year : 2008
Volume : 51
Issue : 16
First Page : 5125
Last Page : 5129
Authors : Pasquini S, Mugnaini C, Tintori C, Botta M, Trejos A, Arvela RK, Larhed M, Witvrouw M, Michiels M, Christ F, Debyser Z, Corelli F.
Abstract : A set of 4-quinolone-3-carboxylic acids bearing different substituents on the condensed benzene ring was designed and synthesized as potential HIV-1 integrase inhibitors structurally related to elvitegravir. Some of the new compounds proved to be able to inhibit the strand transfer step of the virus integration process in the micromolar range. Docking studies and quantum mechanics calculations were used to rationalize these data.
|
Antiviral activity against HIV1 3B in MT4 cells assessed as inhibition of virus-induced cytopathic effect by MTT assay
|
Human immunodeficiency virus 1
|
0.37
nM
|
|
Journal : J. Med. Chem.
Title : Investigations on the 4-quinolone-3-carboxylic acid motif. 1. Synthesis and structure-activity relationship of a class of human immunodeficiency virus type 1 integrase inhibitors.
Year : 2008
Volume : 51
Issue : 16
First Page : 5125
Last Page : 5129
Authors : Pasquini S, Mugnaini C, Tintori C, Botta M, Trejos A, Arvela RK, Larhed M, Witvrouw M, Michiels M, Christ F, Debyser Z, Corelli F.
Abstract : A set of 4-quinolone-3-carboxylic acids bearing different substituents on the condensed benzene ring was designed and synthesized as potential HIV-1 integrase inhibitors structurally related to elvitegravir. Some of the new compounds proved to be able to inhibit the strand transfer step of the virus integration process in the micromolar range. Docking studies and quantum mechanics calculations were used to rationalize these data.
|
Antiviral activity against HIV1
|
Human immunodeficiency virus 1
|
0.9
nM
|
|
Journal : J. Med. Chem.
Title : Investigations on the 4-quinolone-3-carboxylic acid motif. 1. Synthesis and structure-activity relationship of a class of human immunodeficiency virus type 1 integrase inhibitors.
Year : 2008
Volume : 51
Issue : 16
First Page : 5125
Last Page : 5129
Authors : Pasquini S, Mugnaini C, Tintori C, Botta M, Trejos A, Arvela RK, Larhed M, Witvrouw M, Michiels M, Christ F, Debyser Z, Corelli F.
Abstract : A set of 4-quinolone-3-carboxylic acids bearing different substituents on the condensed benzene ring was designed and synthesized as potential HIV-1 integrase inhibitors structurally related to elvitegravir. Some of the new compounds proved to be able to inhibit the strand transfer step of the virus integration process in the micromolar range. Docking studies and quantum mechanics calculations were used to rationalize these data.
|
Inhibition of HIV1 integrase
|
Human immunodeficiency virus 1
|
4.0
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and biological evaluation of a series of 2-hydroxyisoquinoline-1,3(2H,4H)-diones as dual inhibitors of human immunodeficiency virus type 1 integrase and the reverse transcriptase RNase H domain.
Year : 2008
Volume : 51
Issue : 24
First Page : 7717
Last Page : 7730
Authors : Billamboz M, Bailly F, Barreca ML, De Luca L, Mouscadet JF, Calmels C, Andréola ML, Witvrouw M, Christ F, Debyser Z, Cotelle P.
Abstract : We report herein the synthesis of a series of 19 2-hydroxyisoquinoline-1,3(2H,4H)-dione derivatives variously substituted at position 7 aimed at inhibiting selectively two-metal ion catalytic active sites. The compounds were tested against HIV-1 reverse transcriptase (RT) polymerase, HIV-1 RT ribonuclease H (RNase H), and HIV-1 integrase (IN). Most compounds displayed poor inhibition of RT polymerase even at 50 microM. The majority of the synthesized compounds inhibited RNase H and IN at micromolar concentrations, and some of them were weakly selective for IN. Surprisingly, two new hits were discovered, which displayed a high selectivity for IN with submicromolar IC50 values. These enzymatic inhibitory properties may be related to the metal binding abilities of the compounds. Physicochemical studies were consistent with a 1/1 stoichiometry of the magnesium complexes in solution, and the metal complexation was strictly dependent on the enolization abilities of the compounds. Unfortunately, all tested compounds exhibited high cellular cytotoxicity in cell culture which limits their applications as antiviral agents.
|
Inhibition of HIV1 integrase 3'-end processing activity
|
Human immunodeficiency virus 1
|
50.0
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and biological evaluation of a series of 2-hydroxyisoquinoline-1,3(2H,4H)-diones as dual inhibitors of human immunodeficiency virus type 1 integrase and the reverse transcriptase RNase H domain.
Year : 2008
Volume : 51
Issue : 24
First Page : 7717
Last Page : 7730
Authors : Billamboz M, Bailly F, Barreca ML, De Luca L, Mouscadet JF, Calmels C, Andréola ML, Witvrouw M, Christ F, Debyser Z, Cotelle P.
Abstract : We report herein the synthesis of a series of 19 2-hydroxyisoquinoline-1,3(2H,4H)-dione derivatives variously substituted at position 7 aimed at inhibiting selectively two-metal ion catalytic active sites. The compounds were tested against HIV-1 reverse transcriptase (RT) polymerase, HIV-1 RT ribonuclease H (RNase H), and HIV-1 integrase (IN). Most compounds displayed poor inhibition of RT polymerase even at 50 microM. The majority of the synthesized compounds inhibited RNase H and IN at micromolar concentrations, and some of them were weakly selective for IN. Surprisingly, two new hits were discovered, which displayed a high selectivity for IN with submicromolar IC50 values. These enzymatic inhibitory properties may be related to the metal binding abilities of the compounds. Physicochemical studies were consistent with a 1/1 stoichiometry of the magnesium complexes in solution, and the metal complexation was strictly dependent on the enolization abilities of the compounds. Unfortunately, all tested compounds exhibited high cellular cytotoxicity in cell culture which limits their applications as antiviral agents.
|
Inhibition of HIV1 integrase strand transfer activity
|
Human immunodeficiency virus 1
|
7.0
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and biological evaluation of a series of 2-hydroxyisoquinoline-1,3(2H,4H)-diones as dual inhibitors of human immunodeficiency virus type 1 integrase and the reverse transcriptase RNase H domain.
Year : 2008
Volume : 51
Issue : 24
First Page : 7717
Last Page : 7730
Authors : Billamboz M, Bailly F, Barreca ML, De Luca L, Mouscadet JF, Calmels C, Andréola ML, Witvrouw M, Christ F, Debyser Z, Cotelle P.
Abstract : We report herein the synthesis of a series of 19 2-hydroxyisoquinoline-1,3(2H,4H)-dione derivatives variously substituted at position 7 aimed at inhibiting selectively two-metal ion catalytic active sites. The compounds were tested against HIV-1 reverse transcriptase (RT) polymerase, HIV-1 RT ribonuclease H (RNase H), and HIV-1 integrase (IN). Most compounds displayed poor inhibition of RT polymerase even at 50 microM. The majority of the synthesized compounds inhibited RNase H and IN at micromolar concentrations, and some of them were weakly selective for IN. Surprisingly, two new hits were discovered, which displayed a high selectivity for IN with submicromolar IC50 values. These enzymatic inhibitory properties may be related to the metal binding abilities of the compounds. Physicochemical studies were consistent with a 1/1 stoichiometry of the magnesium complexes in solution, and the metal complexation was strictly dependent on the enolization abilities of the compounds. Unfortunately, all tested compounds exhibited high cellular cytotoxicity in cell culture which limits their applications as antiviral agents.
|
Antiviral activity against HIV1 3B infected in human MT4 cells assessed as inhibition of viral replication after 5 days by MTT assay
|
Human immunodeficiency virus 1
|
900.0
nM
|
|
Journal : J. Med. Chem.
Title : Quinolone carboxylic acids as a novel monoketo acid class of human immunodeficiency virus type 1 integrase inhibitors.
Year : 2009
Volume : 52
Issue : 15
First Page : 4869
Last Page : 4882
Authors : Sato M, Kawakami H, Motomura T, Aramaki H, Matsuda T, Yamashita M, Ito Y, Matsuzaki Y, Yamataka K, Ikeda S, Shinkai H.
Abstract : Human immunodeficiency virus type 1 (HIV-1) integrase is a crucial target for antiretroviral drugs, and several keto-enol acid class (often referred to as diketo acid class) inhibitors have clinically exhibited marked antiretroviral activity. Here, we show the synthesis and the detailed structure-activity relationship of the quinolone carboxylic acids as a novel monoketo acid class of integrase inhibitors. 6-(3-Chloro-2-fluorobenzyl)-1-((2S)-1-hydroxy-3,3-dimethylbutan-2-yl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 51, which showed an IC50 of 5.8 nM in the strand transfer assay and an ED50 of 0.6 nM in the antiviral assay, and 6-(3-chloro-2-fluorobenzyl)-1-((2S)-1-hydroxy-3-methylbutan-2-yl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 49, which had an IC50 of 7.2 nM and an ED50 of 0.9 nM, were the most potent compounds in this class. The monoketo acid 49 was much more potent at inhibiting integrase-catalyzed strand transfer processes than 3'-processing reactions, as is the case with the keto-enol acids. Elvitegravir 49 was chosen as a candidate for further studies and is currently in phase 3 clinical trials.
|
Inhibition of HIV-1 integrase
|
Human immunodeficiency virus 1
|
7.244
nM
|
|
Journal : Eur. J. Med. Chem.
Title : CoMFA and CoMSIA 3D-QSAR studies on quionolone caroxylic acid derivatives inhibitors of HIV-1 integrase.
Year : 2010
Volume : 45
Issue : 8
First Page : 3413
Last Page : 3419
Authors : Lu P, Wei X, Zhang R.
Abstract : A series of quionolone caroxylic acid derivatives inhibitors of HIV-1 integrase were subjected to three-dimensional quantitative structure-activity relationship (3D-QSAR) studies using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) approaches. The CoMFA model includes steric and electrostatic fields for the training set with the cross-validated q(2) value of 0.67 and the non-cross-validated r(2) value of 0.98. The cross-validated q(2) value of CoMSIA Model is 0.76 and the non-cross-vaildated r(2) value is 0.99. From the cross-validated results, it can be seen that the CoMSIA model has a better predictive ability than CoMFA model. Based on the above results, the CoMFA and CoMSIA analyses can be used in the design of more potent HIV-1 integrase inhibitors.
|
Inhibition of HIV1 integrase
|
Human immunodeficiency virus 1
|
4.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : New chloro,fluorobenzylindole derivatives as integrase strand-transfer inhibitors (INSTIs) and their mode of action.
Year : 2010
Volume : 18
Issue : 15
First Page : 5510
Last Page : 5518
Authors : Ferro S, De Luca L, Barreca ML, De Grazia S, Christ F, Debyser Z, Chimirri A.
Abstract : The life cycle of HIV-1 requires extensive assistance from the integrase (IN) enzyme which therefore constitutes an attractive therapeutic target for the development of anti-AIDS agents. We herein report the synthesis and biological evaluation of new HIV integrase strand-transfer inhibitors (INSTIs) which proved to be also potent anti-HIV agents. The binding mode of the most representative molecules were also studied by induced-fit docking (IFD). The obtained IFD results were consistent with the mechanism of action proposed for this class of IN inhibitors, that is metal chelating/binding agents.
|
Inhibition of HIV1 integrase strand transfer
|
Human immunodeficiency virus 1
|
15.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : New chloro,fluorobenzylindole derivatives as integrase strand-transfer inhibitors (INSTIs) and their mode of action.
Year : 2010
Volume : 18
Issue : 15
First Page : 5510
Last Page : 5518
Authors : Ferro S, De Luca L, Barreca ML, De Grazia S, Christ F, Debyser Z, Chimirri A.
Abstract : The life cycle of HIV-1 requires extensive assistance from the integrase (IN) enzyme which therefore constitutes an attractive therapeutic target for the development of anti-AIDS agents. We herein report the synthesis and biological evaluation of new HIV integrase strand-transfer inhibitors (INSTIs) which proved to be also potent anti-HIV agents. The binding mode of the most representative molecules were also studied by induced-fit docking (IFD). The obtained IFD results were consistent with the mechanism of action proposed for this class of IN inhibitors, that is metal chelating/binding agents.
|
Antiviral activity against HIV1 infected in human MT4 cells assessed as inhibition of virus-induced cytopathic effect
|
Human immunodeficiency virus 1
|
0.8
nM
|
|
Journal : Bioorg. Med. Chem.
Title : New chloro,fluorobenzylindole derivatives as integrase strand-transfer inhibitors (INSTIs) and their mode of action.
Year : 2010
Volume : 18
Issue : 15
First Page : 5510
Last Page : 5518
Authors : Ferro S, De Luca L, Barreca ML, De Grazia S, Christ F, Debyser Z, Chimirri A.
Abstract : The life cycle of HIV-1 requires extensive assistance from the integrase (IN) enzyme which therefore constitutes an attractive therapeutic target for the development of anti-AIDS agents. We herein report the synthesis and biological evaluation of new HIV integrase strand-transfer inhibitors (INSTIs) which proved to be also potent anti-HIV agents. The binding mode of the most representative molecules were also studied by induced-fit docking (IFD). The obtained IFD results were consistent with the mechanism of action proposed for this class of IN inhibitors, that is metal chelating/binding agents.
|
Antiviral activity against Human immunodeficiency virus 1 3B infected in human MT-4 cells assessed as inhibition of viral replication
|
Human immunodeficiency virus 1
|
2.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : The naphthyridinone GSK364735 is a novel, potent human immunodeficiency virus type 1 integrase inhibitor and antiretroviral.
Year : 2008
Volume : 52
Issue : 3
First Page : 901
Last Page : 908
Authors : Garvey EP, Johns BA, Gartland MJ, Foster SA, Miller WH, Ferris RG, Hazen RJ, Underwood MR, Boros EE, Thompson JB, Weatherhead JG, Koble CS, Allen SH, Schaller LT, Sherrill RG, Yoshinaga T, Kobayashi M, Wakasa-Morimoto C, Miki S, Nakahara K, Noshi T, Sato A, Fujiwara T.
Abstract : The naphthyridinone GSK364735 potently inhibited recombinant human immunodeficiency virus type 1 (HIV-1) integrase in a strand transfer assay (mean 50% inhibitory concentration +/- standard deviation, 8 +/- 2 nM). As expected based on the structure of the drug, it bound competitively with another two-metal binding inhibitor (Kd [binding constant], 6 +/- 4 nM). In a number of different cellular assays, GSK364735 inhibited HIV replication with potency at nanomolar concentrations (e.g., in peripheral blood mononuclear cells and MT-4 cells, 50% effective concentrations were 1.2 +/- 0.4 and 5 +/- 1 nM, respectively), with selectivity indexes of antiviral activity versus in-assay cytotoxicity of at least 2,200. When human serum was added, the antiviral potency decreased (e.g., a 35-fold decrease in the presence of 100% human serum was calculated by extrapolation from the results of the MT-4 cell assay). In cellular assays, GSK364735 blocked viral DNA integration, with a concomitant increase in two-long-terminal-repeat circles. As expected, this integrase inhibitor was equally active against wild-type viruses and mutant viruses resistant to approved drugs targeting either reverse transcriptase or protease. In contrast, some but not all viruses resistant to other integrase inhibitors were resistant to GSK364735. When virus was passaged in the presence of the inhibitor, we identified resistance mutations within the integrase active site that were the same as or similar to mutations arising in response to other two-metal binding inhibitors. Finally, either additive or synergistic effects were observed when GSK364735 was tested in combination with approved antiretrovirals (i.e., no antagonistic effects were seen). Thus, based on all the data, GSK364735 exerted potent antiviral activity through the inhibition of viral DNA integration by interacting at the two-metal binding site within the catalytic center of HIV integrase.
|
Antiviral activity against Human immunodeficiency virus 1 Ba-L infected in human PBMCs assessed as inhibition of viral replication
|
Human immunodeficiency virus 1
|
2.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : The naphthyridinone GSK364735 is a novel, potent human immunodeficiency virus type 1 integrase inhibitor and antiretroviral.
Year : 2008
Volume : 52
Issue : 3
First Page : 901
Last Page : 908
Authors : Garvey EP, Johns BA, Gartland MJ, Foster SA, Miller WH, Ferris RG, Hazen RJ, Underwood MR, Boros EE, Thompson JB, Weatherhead JG, Koble CS, Allen SH, Schaller LT, Sherrill RG, Yoshinaga T, Kobayashi M, Wakasa-Morimoto C, Miki S, Nakahara K, Noshi T, Sato A, Fujiwara T.
Abstract : The naphthyridinone GSK364735 potently inhibited recombinant human immunodeficiency virus type 1 (HIV-1) integrase in a strand transfer assay (mean 50% inhibitory concentration +/- standard deviation, 8 +/- 2 nM). As expected based on the structure of the drug, it bound competitively with another two-metal binding inhibitor (Kd [binding constant], 6 +/- 4 nM). In a number of different cellular assays, GSK364735 inhibited HIV replication with potency at nanomolar concentrations (e.g., in peripheral blood mononuclear cells and MT-4 cells, 50% effective concentrations were 1.2 +/- 0.4 and 5 +/- 1 nM, respectively), with selectivity indexes of antiviral activity versus in-assay cytotoxicity of at least 2,200. When human serum was added, the antiviral potency decreased (e.g., a 35-fold decrease in the presence of 100% human serum was calculated by extrapolation from the results of the MT-4 cell assay). In cellular assays, GSK364735 blocked viral DNA integration, with a concomitant increase in two-long-terminal-repeat circles. As expected, this integrase inhibitor was equally active against wild-type viruses and mutant viruses resistant to approved drugs targeting either reverse transcriptase or protease. In contrast, some but not all viruses resistant to other integrase inhibitors were resistant to GSK364735. When virus was passaged in the presence of the inhibitor, we identified resistance mutations within the integrase active site that were the same as or similar to mutations arising in response to other two-metal binding inhibitors. Finally, either additive or synergistic effects were observed when GSK364735 was tested in combination with approved antiretrovirals (i.e., no antagonistic effects were seen). Thus, based on all the data, GSK364735 exerted potent antiviral activity through the inhibition of viral DNA integration by interacting at the two-metal binding site within the catalytic center of HIV integrase.
|
Displacement of 20 nM [3H]GSK304649 from Human immunodeficiency virus 1 integrase by scintillation proximity assay
|
Human immunodeficiency virus 1
|
11.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : The naphthyridinone GSK364735 is a novel, potent human immunodeficiency virus type 1 integrase inhibitor and antiretroviral.
Year : 2008
Volume : 52
Issue : 3
First Page : 901
Last Page : 908
Authors : Garvey EP, Johns BA, Gartland MJ, Foster SA, Miller WH, Ferris RG, Hazen RJ, Underwood MR, Boros EE, Thompson JB, Weatherhead JG, Koble CS, Allen SH, Schaller LT, Sherrill RG, Yoshinaga T, Kobayashi M, Wakasa-Morimoto C, Miki S, Nakahara K, Noshi T, Sato A, Fujiwara T.
Abstract : The naphthyridinone GSK364735 potently inhibited recombinant human immunodeficiency virus type 1 (HIV-1) integrase in a strand transfer assay (mean 50% inhibitory concentration +/- standard deviation, 8 +/- 2 nM). As expected based on the structure of the drug, it bound competitively with another two-metal binding inhibitor (Kd [binding constant], 6 +/- 4 nM). In a number of different cellular assays, GSK364735 inhibited HIV replication with potency at nanomolar concentrations (e.g., in peripheral blood mononuclear cells and MT-4 cells, 50% effective concentrations were 1.2 +/- 0.4 and 5 +/- 1 nM, respectively), with selectivity indexes of antiviral activity versus in-assay cytotoxicity of at least 2,200. When human serum was added, the antiviral potency decreased (e.g., a 35-fold decrease in the presence of 100% human serum was calculated by extrapolation from the results of the MT-4 cell assay). In cellular assays, GSK364735 blocked viral DNA integration, with a concomitant increase in two-long-terminal-repeat circles. As expected, this integrase inhibitor was equally active against wild-type viruses and mutant viruses resistant to approved drugs targeting either reverse transcriptase or protease. In contrast, some but not all viruses resistant to other integrase inhibitors were resistant to GSK364735. When virus was passaged in the presence of the inhibitor, we identified resistance mutations within the integrase active site that were the same as or similar to mutations arising in response to other two-metal binding inhibitors. Finally, either additive or synergistic effects were observed when GSK364735 was tested in combination with approved antiretrovirals (i.e., no antagonistic effects were seen). Thus, based on all the data, GSK364735 exerted potent antiviral activity through the inhibition of viral DNA integration by interacting at the two-metal binding site within the catalytic center of HIV integrase.
|
Inhibition of Human immunodeficiency virus 1 integrase by strand transfer scintillation proximity assay
|
Human immunodeficiency virus 1
|
6.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : The naphthyridinone GSK364735 is a novel, potent human immunodeficiency virus type 1 integrase inhibitor and antiretroviral.
Year : 2008
Volume : 52
Issue : 3
First Page : 901
Last Page : 908
Authors : Garvey EP, Johns BA, Gartland MJ, Foster SA, Miller WH, Ferris RG, Hazen RJ, Underwood MR, Boros EE, Thompson JB, Weatherhead JG, Koble CS, Allen SH, Schaller LT, Sherrill RG, Yoshinaga T, Kobayashi M, Wakasa-Morimoto C, Miki S, Nakahara K, Noshi T, Sato A, Fujiwara T.
Abstract : The naphthyridinone GSK364735 potently inhibited recombinant human immunodeficiency virus type 1 (HIV-1) integrase in a strand transfer assay (mean 50% inhibitory concentration +/- standard deviation, 8 +/- 2 nM). As expected based on the structure of the drug, it bound competitively with another two-metal binding inhibitor (Kd [binding constant], 6 +/- 4 nM). In a number of different cellular assays, GSK364735 inhibited HIV replication with potency at nanomolar concentrations (e.g., in peripheral blood mononuclear cells and MT-4 cells, 50% effective concentrations were 1.2 +/- 0.4 and 5 +/- 1 nM, respectively), with selectivity indexes of antiviral activity versus in-assay cytotoxicity of at least 2,200. When human serum was added, the antiviral potency decreased (e.g., a 35-fold decrease in the presence of 100% human serum was calculated by extrapolation from the results of the MT-4 cell assay). In cellular assays, GSK364735 blocked viral DNA integration, with a concomitant increase in two-long-terminal-repeat circles. As expected, this integrase inhibitor was equally active against wild-type viruses and mutant viruses resistant to approved drugs targeting either reverse transcriptase or protease. In contrast, some but not all viruses resistant to other integrase inhibitors were resistant to GSK364735. When virus was passaged in the presence of the inhibitor, we identified resistance mutations within the integrase active site that were the same as or similar to mutations arising in response to other two-metal binding inhibitors. Finally, either additive or synergistic effects were observed when GSK364735 was tested in combination with approved antiretrovirals (i.e., no antagonistic effects were seen). Thus, based on all the data, GSK364735 exerted potent antiviral activity through the inhibition of viral DNA integration by interacting at the two-metal binding site within the catalytic center of HIV integrase.
|
Antiviral activity against vesicular stomatitis virus G-pseudotyped Human immunodeficiency virus infected in human MT-4 cells assessed as inhibition of viral replication
|
Human immunodeficiency virus
|
1.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : The naphthyridinone GSK364735 is a novel, potent human immunodeficiency virus type 1 integrase inhibitor and antiretroviral.
Year : 2008
Volume : 52
Issue : 3
First Page : 901
Last Page : 908
Authors : Garvey EP, Johns BA, Gartland MJ, Foster SA, Miller WH, Ferris RG, Hazen RJ, Underwood MR, Boros EE, Thompson JB, Weatherhead JG, Koble CS, Allen SH, Schaller LT, Sherrill RG, Yoshinaga T, Kobayashi M, Wakasa-Morimoto C, Miki S, Nakahara K, Noshi T, Sato A, Fujiwara T.
Abstract : The naphthyridinone GSK364735 potently inhibited recombinant human immunodeficiency virus type 1 (HIV-1) integrase in a strand transfer assay (mean 50% inhibitory concentration +/- standard deviation, 8 +/- 2 nM). As expected based on the structure of the drug, it bound competitively with another two-metal binding inhibitor (Kd [binding constant], 6 +/- 4 nM). In a number of different cellular assays, GSK364735 inhibited HIV replication with potency at nanomolar concentrations (e.g., in peripheral blood mononuclear cells and MT-4 cells, 50% effective concentrations were 1.2 +/- 0.4 and 5 +/- 1 nM, respectively), with selectivity indexes of antiviral activity versus in-assay cytotoxicity of at least 2,200. When human serum was added, the antiviral potency decreased (e.g., a 35-fold decrease in the presence of 100% human serum was calculated by extrapolation from the results of the MT-4 cell assay). In cellular assays, GSK364735 blocked viral DNA integration, with a concomitant increase in two-long-terminal-repeat circles. As expected, this integrase inhibitor was equally active against wild-type viruses and mutant viruses resistant to approved drugs targeting either reverse transcriptase or protease. In contrast, some but not all viruses resistant to other integrase inhibitors were resistant to GSK364735. When virus was passaged in the presence of the inhibitor, we identified resistance mutations within the integrase active site that were the same as or similar to mutations arising in response to other two-metal binding inhibitors. Finally, either additive or synergistic effects were observed when GSK364735 was tested in combination with approved antiretrovirals (i.e., no antagonistic effects were seen). Thus, based on all the data, GSK364735 exerted potent antiviral activity through the inhibition of viral DNA integration by interacting at the two-metal binding site within the catalytic center of HIV integrase.
|
Antiviral activity against HIV 1 3B infected in MT-4 cells assessed as inhibition of virus-induced cytopathic effect by MTT assay
|
Human immunodeficiency virus 1
|
1.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Mutations in human immunodeficiency virus type 1 integrase confer resistance to the naphthyridine L-870,810 and cross-resistance to the clinical trial drug GS-9137.
Year : 2008
Volume : 52
Issue : 6
First Page : 2069
Last Page : 2078
Authors : Hombrouck A, Voet A, Van Remoortel B, Desadeleer C, De Maeyer M, Debyser Z, Witvrouw M.
Abstract : To gain further insight into the understanding of the antiviral resistance patterns and mechanisms of the integrase strand transfer inhibitor L-870,810, the prototypical naphthyridine analogue, we passaged the human immunodeficiency virus type 1 strain HIV-1(III(B)) in cell culture in the presence of increasing concentrations of L-870,810 (III(B)/L-870,810). The mutations L74M, E92Q, and S230N were successively selected in the integrase. The L74M and E92Q mutations have both been associated in the past with resistance against the diketo acid (DKA) analogues L-708,906 and S-1360 and the clinical trial drugs MK-0518 and GS-9137. After 20, 40, and 60 passages in the presence of L-870,810, III(B)/L-870,810 displayed 22-, 34-, and 110-fold reduced susceptibility to L-870,810, respectively. Phenotypic cross-resistance against the DKA analogue CHI-1043 and MK-0518 was modest but that against GS-9137 was pronounced. Recombination of the mutant integrase genes into the wild-type background reproduced the resistance profile of the resistant III(B)/L-870,810 strains. In addition, resistance against L-870,810 was accompanied by reduced viral replication kinetics and reduced enzymatic activity of integrase. In conclusion, the accumulation of L74M, E92Q, and S230N mutations in the integrase causes resistance to the naphthyridine L-870,810 and cross-resistance to GS-9137. These data may have implications for cross-resistance of different integrase inhibitors in the clinic.
|
Antiviral activity against HIV 1 3B harboring integrase E92Q S230N double mutant infected in MT-4 cells assessed as inhibition of virus-induced cytopathic effect by MTT assay selected after 20 passages in presence of compound
|
Human immunodeficiency virus 1
|
33.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Mutations in human immunodeficiency virus type 1 integrase confer resistance to the naphthyridine L-870,810 and cross-resistance to the clinical trial drug GS-9137.
Year : 2008
Volume : 52
Issue : 6
First Page : 2069
Last Page : 2078
Authors : Hombrouck A, Voet A, Van Remoortel B, Desadeleer C, De Maeyer M, Debyser Z, Witvrouw M.
Abstract : To gain further insight into the understanding of the antiviral resistance patterns and mechanisms of the integrase strand transfer inhibitor L-870,810, the prototypical naphthyridine analogue, we passaged the human immunodeficiency virus type 1 strain HIV-1(III(B)) in cell culture in the presence of increasing concentrations of L-870,810 (III(B)/L-870,810). The mutations L74M, E92Q, and S230N were successively selected in the integrase. The L74M and E92Q mutations have both been associated in the past with resistance against the diketo acid (DKA) analogues L-708,906 and S-1360 and the clinical trial drugs MK-0518 and GS-9137. After 20, 40, and 60 passages in the presence of L-870,810, III(B)/L-870,810 displayed 22-, 34-, and 110-fold reduced susceptibility to L-870,810, respectively. Phenotypic cross-resistance against the DKA analogue CHI-1043 and MK-0518 was modest but that against GS-9137 was pronounced. Recombination of the mutant integrase genes into the wild-type background reproduced the resistance profile of the resistant III(B)/L-870,810 strains. In addition, resistance against L-870,810 was accompanied by reduced viral replication kinetics and reduced enzymatic activity of integrase. In conclusion, the accumulation of L74M, E92Q, and S230N mutations in the integrase causes resistance to the naphthyridine L-870,810 and cross-resistance to GS-9137. These data may have implications for cross-resistance of different integrase inhibitors in the clinic.
|
Antiviral activity against HIV 1 3B harboring integrase L34M mutant infected in MT-4 cells assessed as inhibition of virus-induced cytopathic effect by MTT assay selected after 40 passages in presence of compound
|
Human immunodeficiency virus 1
|
50.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Mutations in human immunodeficiency virus type 1 integrase confer resistance to the naphthyridine L-870,810 and cross-resistance to the clinical trial drug GS-9137.
Year : 2008
Volume : 52
Issue : 6
First Page : 2069
Last Page : 2078
Authors : Hombrouck A, Voet A, Van Remoortel B, Desadeleer C, De Maeyer M, Debyser Z, Witvrouw M.
Abstract : To gain further insight into the understanding of the antiviral resistance patterns and mechanisms of the integrase strand transfer inhibitor L-870,810, the prototypical naphthyridine analogue, we passaged the human immunodeficiency virus type 1 strain HIV-1(III(B)) in cell culture in the presence of increasing concentrations of L-870,810 (III(B)/L-870,810). The mutations L74M, E92Q, and S230N were successively selected in the integrase. The L74M and E92Q mutations have both been associated in the past with resistance against the diketo acid (DKA) analogues L-708,906 and S-1360 and the clinical trial drugs MK-0518 and GS-9137. After 20, 40, and 60 passages in the presence of L-870,810, III(B)/L-870,810 displayed 22-, 34-, and 110-fold reduced susceptibility to L-870,810, respectively. Phenotypic cross-resistance against the DKA analogue CHI-1043 and MK-0518 was modest but that against GS-9137 was pronounced. Recombination of the mutant integrase genes into the wild-type background reproduced the resistance profile of the resistant III(B)/L-870,810 strains. In addition, resistance against L-870,810 was accompanied by reduced viral replication kinetics and reduced enzymatic activity of integrase. In conclusion, the accumulation of L74M, E92Q, and S230N mutations in the integrase causes resistance to the naphthyridine L-870,810 and cross-resistance to GS-9137. These data may have implications for cross-resistance of different integrase inhibitors in the clinic.
|
Antiviral activity against HIV 1 3B harboring integrase E92Q, S230N and L34M triple mutant infected in MT-4 cells assessed as inhibition of virus-induced cytopathic effect by MTT assay selected after 60 passages in presence of compound
|
Human immunodeficiency virus 1
|
77.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Mutations in human immunodeficiency virus type 1 integrase confer resistance to the naphthyridine L-870,810 and cross-resistance to the clinical trial drug GS-9137.
Year : 2008
Volume : 52
Issue : 6
First Page : 2069
Last Page : 2078
Authors : Hombrouck A, Voet A, Van Remoortel B, Desadeleer C, De Maeyer M, Debyser Z, Witvrouw M.
Abstract : To gain further insight into the understanding of the antiviral resistance patterns and mechanisms of the integrase strand transfer inhibitor L-870,810, the prototypical naphthyridine analogue, we passaged the human immunodeficiency virus type 1 strain HIV-1(III(B)) in cell culture in the presence of increasing concentrations of L-870,810 (III(B)/L-870,810). The mutations L74M, E92Q, and S230N were successively selected in the integrase. The L74M and E92Q mutations have both been associated in the past with resistance against the diketo acid (DKA) analogues L-708,906 and S-1360 and the clinical trial drugs MK-0518 and GS-9137. After 20, 40, and 60 passages in the presence of L-870,810, III(B)/L-870,810 displayed 22-, 34-, and 110-fold reduced susceptibility to L-870,810, respectively. Phenotypic cross-resistance against the DKA analogue CHI-1043 and MK-0518 was modest but that against GS-9137 was pronounced. Recombination of the mutant integrase genes into the wild-type background reproduced the resistance profile of the resistant III(B)/L-870,810 strains. In addition, resistance against L-870,810 was accompanied by reduced viral replication kinetics and reduced enzymatic activity of integrase. In conclusion, the accumulation of L74M, E92Q, and S230N mutations in the integrase causes resistance to the naphthyridine L-870,810 and cross-resistance to GS-9137. These data may have implications for cross-resistance of different integrase inhibitors in the clinic.
|
Antiviral activity against HIV 1 RIN harboring integrase gene infected in MT-4 cells assessed as inhibition of virus-induced cytopathic effect by MTT assay
|
Human immunodeficiency virus 1
|
0.7
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Mutations in human immunodeficiency virus type 1 integrase confer resistance to the naphthyridine L-870,810 and cross-resistance to the clinical trial drug GS-9137.
Year : 2008
Volume : 52
Issue : 6
First Page : 2069
Last Page : 2078
Authors : Hombrouck A, Voet A, Van Remoortel B, Desadeleer C, De Maeyer M, Debyser Z, Witvrouw M.
Abstract : To gain further insight into the understanding of the antiviral resistance patterns and mechanisms of the integrase strand transfer inhibitor L-870,810, the prototypical naphthyridine analogue, we passaged the human immunodeficiency virus type 1 strain HIV-1(III(B)) in cell culture in the presence of increasing concentrations of L-870,810 (III(B)/L-870,810). The mutations L74M, E92Q, and S230N were successively selected in the integrase. The L74M and E92Q mutations have both been associated in the past with resistance against the diketo acid (DKA) analogues L-708,906 and S-1360 and the clinical trial drugs MK-0518 and GS-9137. After 20, 40, and 60 passages in the presence of L-870,810, III(B)/L-870,810 displayed 22-, 34-, and 110-fold reduced susceptibility to L-870,810, respectively. Phenotypic cross-resistance against the DKA analogue CHI-1043 and MK-0518 was modest but that against GS-9137 was pronounced. Recombination of the mutant integrase genes into the wild-type background reproduced the resistance profile of the resistant III(B)/L-870,810 strains. In addition, resistance against L-870,810 was accompanied by reduced viral replication kinetics and reduced enzymatic activity of integrase. In conclusion, the accumulation of L74M, E92Q, and S230N mutations in the integrase causes resistance to the naphthyridine L-870,810 and cross-resistance to GS-9137. These data may have implications for cross-resistance of different integrase inhibitors in the clinic.
|
Antiviral activity against HIV 1 RIN harboring integrase gene infected in MT-4 cells assessed as inhibition of virus-induced cytopathic effect by MTT assay after 20 passages selected in presence of compound
|
Human immunodeficiency virus 1
|
15.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Mutations in human immunodeficiency virus type 1 integrase confer resistance to the naphthyridine L-870,810 and cross-resistance to the clinical trial drug GS-9137.
Year : 2008
Volume : 52
Issue : 6
First Page : 2069
Last Page : 2078
Authors : Hombrouck A, Voet A, Van Remoortel B, Desadeleer C, De Maeyer M, Debyser Z, Witvrouw M.
Abstract : To gain further insight into the understanding of the antiviral resistance patterns and mechanisms of the integrase strand transfer inhibitor L-870,810, the prototypical naphthyridine analogue, we passaged the human immunodeficiency virus type 1 strain HIV-1(III(B)) in cell culture in the presence of increasing concentrations of L-870,810 (III(B)/L-870,810). The mutations L74M, E92Q, and S230N were successively selected in the integrase. The L74M and E92Q mutations have both been associated in the past with resistance against the diketo acid (DKA) analogues L-708,906 and S-1360 and the clinical trial drugs MK-0518 and GS-9137. After 20, 40, and 60 passages in the presence of L-870,810, III(B)/L-870,810 displayed 22-, 34-, and 110-fold reduced susceptibility to L-870,810, respectively. Phenotypic cross-resistance against the DKA analogue CHI-1043 and MK-0518 was modest but that against GS-9137 was pronounced. Recombination of the mutant integrase genes into the wild-type background reproduced the resistance profile of the resistant III(B)/L-870,810 strains. In addition, resistance against L-870,810 was accompanied by reduced viral replication kinetics and reduced enzymatic activity of integrase. In conclusion, the accumulation of L74M, E92Q, and S230N mutations in the integrase causes resistance to the naphthyridine L-870,810 and cross-resistance to GS-9137. These data may have implications for cross-resistance of different integrase inhibitors in the clinic.
|
Antiviral activity against HIV 1 RIN HIV 1 RIN harboring integrase gene infected in MT-4 cells assessed as inhibition of virus-induced cytopathic effect by MTT assay after 40 passages selected in presence of compound
|
Human immunodeficiency virus 1
|
18.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Mutations in human immunodeficiency virus type 1 integrase confer resistance to the naphthyridine L-870,810 and cross-resistance to the clinical trial drug GS-9137.
Year : 2008
Volume : 52
Issue : 6
First Page : 2069
Last Page : 2078
Authors : Hombrouck A, Voet A, Van Remoortel B, Desadeleer C, De Maeyer M, Debyser Z, Witvrouw M.
Abstract : To gain further insight into the understanding of the antiviral resistance patterns and mechanisms of the integrase strand transfer inhibitor L-870,810, the prototypical naphthyridine analogue, we passaged the human immunodeficiency virus type 1 strain HIV-1(III(B)) in cell culture in the presence of increasing concentrations of L-870,810 (III(B)/L-870,810). The mutations L74M, E92Q, and S230N were successively selected in the integrase. The L74M and E92Q mutations have both been associated in the past with resistance against the diketo acid (DKA) analogues L-708,906 and S-1360 and the clinical trial drugs MK-0518 and GS-9137. After 20, 40, and 60 passages in the presence of L-870,810, III(B)/L-870,810 displayed 22-, 34-, and 110-fold reduced susceptibility to L-870,810, respectively. Phenotypic cross-resistance against the DKA analogue CHI-1043 and MK-0518 was modest but that against GS-9137 was pronounced. Recombination of the mutant integrase genes into the wild-type background reproduced the resistance profile of the resistant III(B)/L-870,810 strains. In addition, resistance against L-870,810 was accompanied by reduced viral replication kinetics and reduced enzymatic activity of integrase. In conclusion, the accumulation of L74M, E92Q, and S230N mutations in the integrase causes resistance to the naphthyridine L-870,810 and cross-resistance to GS-9137. These data may have implications for cross-resistance of different integrase inhibitors in the clinic.
|
Antiviral activity against HIV 1 RIN HIV 1 RIN harboring integrase gene infected in MT-4 cells assessed as inhibition of virus-induced cytopathic effect by MTT assay after 60 passages selected in presence of compound
|
Human immunodeficiency virus 1
|
59.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Mutations in human immunodeficiency virus type 1 integrase confer resistance to the naphthyridine L-870,810 and cross-resistance to the clinical trial drug GS-9137.
Year : 2008
Volume : 52
Issue : 6
First Page : 2069
Last Page : 2078
Authors : Hombrouck A, Voet A, Van Remoortel B, Desadeleer C, De Maeyer M, Debyser Z, Witvrouw M.
Abstract : To gain further insight into the understanding of the antiviral resistance patterns and mechanisms of the integrase strand transfer inhibitor L-870,810, the prototypical naphthyridine analogue, we passaged the human immunodeficiency virus type 1 strain HIV-1(III(B)) in cell culture in the presence of increasing concentrations of L-870,810 (III(B)/L-870,810). The mutations L74M, E92Q, and S230N were successively selected in the integrase. The L74M and E92Q mutations have both been associated in the past with resistance against the diketo acid (DKA) analogues L-708,906 and S-1360 and the clinical trial drugs MK-0518 and GS-9137. After 20, 40, and 60 passages in the presence of L-870,810, III(B)/L-870,810 displayed 22-, 34-, and 110-fold reduced susceptibility to L-870,810, respectively. Phenotypic cross-resistance against the DKA analogue CHI-1043 and MK-0518 was modest but that against GS-9137 was pronounced. Recombination of the mutant integrase genes into the wild-type background reproduced the resistance profile of the resistant III(B)/L-870,810 strains. In addition, resistance against L-870,810 was accompanied by reduced viral replication kinetics and reduced enzymatic activity of integrase. In conclusion, the accumulation of L74M, E92Q, and S230N mutations in the integrase causes resistance to the naphthyridine L-870,810 and cross-resistance to GS-9137. These data may have implications for cross-resistance of different integrase inhibitors in the clinic.
|
Antiviral activity against HIV 1 NL4.3 assessed as inhibition of virus-induced cytopathic effect by MTT assay
|
Human immunodeficiency virus 1
|
0.7
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Mutations in human immunodeficiency virus type 1 integrase confer resistance to the naphthyridine L-870,810 and cross-resistance to the clinical trial drug GS-9137.
Year : 2008
Volume : 52
Issue : 6
First Page : 2069
Last Page : 2078
Authors : Hombrouck A, Voet A, Van Remoortel B, Desadeleer C, De Maeyer M, Debyser Z, Witvrouw M.
Abstract : To gain further insight into the understanding of the antiviral resistance patterns and mechanisms of the integrase strand transfer inhibitor L-870,810, the prototypical naphthyridine analogue, we passaged the human immunodeficiency virus type 1 strain HIV-1(III(B)) in cell culture in the presence of increasing concentrations of L-870,810 (III(B)/L-870,810). The mutations L74M, E92Q, and S230N were successively selected in the integrase. The L74M and E92Q mutations have both been associated in the past with resistance against the diketo acid (DKA) analogues L-708,906 and S-1360 and the clinical trial drugs MK-0518 and GS-9137. After 20, 40, and 60 passages in the presence of L-870,810, III(B)/L-870,810 displayed 22-, 34-, and 110-fold reduced susceptibility to L-870,810, respectively. Phenotypic cross-resistance against the DKA analogue CHI-1043 and MK-0518 was modest but that against GS-9137 was pronounced. Recombination of the mutant integrase genes into the wild-type background reproduced the resistance profile of the resistant III(B)/L-870,810 strains. In addition, resistance against L-870,810 was accompanied by reduced viral replication kinetics and reduced enzymatic activity of integrase. In conclusion, the accumulation of L74M, E92Q, and S230N mutations in the integrase causes resistance to the naphthyridine L-870,810 and cross-resistance to GS-9137. These data may have implications for cross-resistance of different integrase inhibitors in the clinic.
|
Antiviral activity against HIV 1 NL4.3 harboring integrase L74M mutant infected in human MT-4 cells assessed as inhibition of virus-induced cytopathic effect by MTT assay
|
Human immunodeficiency virus 1
|
0.6
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Mutations in human immunodeficiency virus type 1 integrase confer resistance to the naphthyridine L-870,810 and cross-resistance to the clinical trial drug GS-9137.
Year : 2008
Volume : 52
Issue : 6
First Page : 2069
Last Page : 2078
Authors : Hombrouck A, Voet A, Van Remoortel B, Desadeleer C, De Maeyer M, Debyser Z, Witvrouw M.
Abstract : To gain further insight into the understanding of the antiviral resistance patterns and mechanisms of the integrase strand transfer inhibitor L-870,810, the prototypical naphthyridine analogue, we passaged the human immunodeficiency virus type 1 strain HIV-1(III(B)) in cell culture in the presence of increasing concentrations of L-870,810 (III(B)/L-870,810). The mutations L74M, E92Q, and S230N were successively selected in the integrase. The L74M and E92Q mutations have both been associated in the past with resistance against the diketo acid (DKA) analogues L-708,906 and S-1360 and the clinical trial drugs MK-0518 and GS-9137. After 20, 40, and 60 passages in the presence of L-870,810, III(B)/L-870,810 displayed 22-, 34-, and 110-fold reduced susceptibility to L-870,810, respectively. Phenotypic cross-resistance against the DKA analogue CHI-1043 and MK-0518 was modest but that against GS-9137 was pronounced. Recombination of the mutant integrase genes into the wild-type background reproduced the resistance profile of the resistant III(B)/L-870,810 strains. In addition, resistance against L-870,810 was accompanied by reduced viral replication kinetics and reduced enzymatic activity of integrase. In conclusion, the accumulation of L74M, E92Q, and S230N mutations in the integrase causes resistance to the naphthyridine L-870,810 and cross-resistance to GS-9137. These data may have implications for cross-resistance of different integrase inhibitors in the clinic.
|
Antiviral activity against HIV 1 NL4.3 integrase E92Q mutant infected in human MT-4 cells assessed as inhibition of virus-induced cytopathic effect by MTT assay
|
Human immunodeficiency virus 1
|
12.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Mutations in human immunodeficiency virus type 1 integrase confer resistance to the naphthyridine L-870,810 and cross-resistance to the clinical trial drug GS-9137.
Year : 2008
Volume : 52
Issue : 6
First Page : 2069
Last Page : 2078
Authors : Hombrouck A, Voet A, Van Remoortel B, Desadeleer C, De Maeyer M, Debyser Z, Witvrouw M.
Abstract : To gain further insight into the understanding of the antiviral resistance patterns and mechanisms of the integrase strand transfer inhibitor L-870,810, the prototypical naphthyridine analogue, we passaged the human immunodeficiency virus type 1 strain HIV-1(III(B)) in cell culture in the presence of increasing concentrations of L-870,810 (III(B)/L-870,810). The mutations L74M, E92Q, and S230N were successively selected in the integrase. The L74M and E92Q mutations have both been associated in the past with resistance against the diketo acid (DKA) analogues L-708,906 and S-1360 and the clinical trial drugs MK-0518 and GS-9137. After 20, 40, and 60 passages in the presence of L-870,810, III(B)/L-870,810 displayed 22-, 34-, and 110-fold reduced susceptibility to L-870,810, respectively. Phenotypic cross-resistance against the DKA analogue CHI-1043 and MK-0518 was modest but that against GS-9137 was pronounced. Recombination of the mutant integrase genes into the wild-type background reproduced the resistance profile of the resistant III(B)/L-870,810 strains. In addition, resistance against L-870,810 was accompanied by reduced viral replication kinetics and reduced enzymatic activity of integrase. In conclusion, the accumulation of L74M, E92Q, and S230N mutations in the integrase causes resistance to the naphthyridine L-870,810 and cross-resistance to GS-9137. These data may have implications for cross-resistance of different integrase inhibitors in the clinic.
|
Antiviral activity against HIV 1 NL4.3 integrase S230N mutant infected in human MT-4 cells assessed as inhibition of virus-induced cytopathic effect by MTT assay
|
Human immunodeficiency virus 1
|
0.9
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Mutations in human immunodeficiency virus type 1 integrase confer resistance to the naphthyridine L-870,810 and cross-resistance to the clinical trial drug GS-9137.
Year : 2008
Volume : 52
Issue : 6
First Page : 2069
Last Page : 2078
Authors : Hombrouck A, Voet A, Van Remoortel B, Desadeleer C, De Maeyer M, Debyser Z, Witvrouw M.
Abstract : To gain further insight into the understanding of the antiviral resistance patterns and mechanisms of the integrase strand transfer inhibitor L-870,810, the prototypical naphthyridine analogue, we passaged the human immunodeficiency virus type 1 strain HIV-1(III(B)) in cell culture in the presence of increasing concentrations of L-870,810 (III(B)/L-870,810). The mutations L74M, E92Q, and S230N were successively selected in the integrase. The L74M and E92Q mutations have both been associated in the past with resistance against the diketo acid (DKA) analogues L-708,906 and S-1360 and the clinical trial drugs MK-0518 and GS-9137. After 20, 40, and 60 passages in the presence of L-870,810, III(B)/L-870,810 displayed 22-, 34-, and 110-fold reduced susceptibility to L-870,810, respectively. Phenotypic cross-resistance against the DKA analogue CHI-1043 and MK-0518 was modest but that against GS-9137 was pronounced. Recombination of the mutant integrase genes into the wild-type background reproduced the resistance profile of the resistant III(B)/L-870,810 strains. In addition, resistance against L-870,810 was accompanied by reduced viral replication kinetics and reduced enzymatic activity of integrase. In conclusion, the accumulation of L74M, E92Q, and S230N mutations in the integrase causes resistance to the naphthyridine L-870,810 and cross-resistance to GS-9137. These data may have implications for cross-resistance of different integrase inhibitors in the clinic.
|
Antiviral activity against VSV-G protein pseudotyped HIV1 luciferase reporter virus in mixture of human HeLa/JC53 cells assessed as luminescence after 48 hrs
|
Human immunodeficiency virus 1
|
0.7
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 6-Benzylamino 4-oxo-1,4-dihydro-1,8-naphthyridines and 4-oxo-1,4-dihydroquinolines as HIV integrase inhibitors.
Year : 2011
Volume : 21
Issue : 2
First Page : 760
Last Page : 763
Authors : Nagasawa JY, Song J, Chen H, Kim HW, Blazel J, Ouk S, Groschel B, Borges V, Ong V, Yeh LT, Girardet JL, Vernier JM, Raney AK, Pinkerton AB.
Abstract : SAR studies on the quinolone carboxylic acid class of HIV-1 integrase inhibitors focused on improving the metabolic stability and led to the discovery of 27 and 38.
|
Antiviral activity against VSV-G protein pseudotyped HIV1 luciferase reporter virus in mixture of human HeLa/JC53 cells assessed as luminescence after 48 hrs in presence of 40% human serum
|
Human immunodeficiency virus 1
|
36.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 6-Benzylamino 4-oxo-1,4-dihydro-1,8-naphthyridines and 4-oxo-1,4-dihydroquinolines as HIV integrase inhibitors.
Year : 2011
Volume : 21
Issue : 2
First Page : 760
Last Page : 763
Authors : Nagasawa JY, Song J, Chen H, Kim HW, Blazel J, Ouk S, Groschel B, Borges V, Ong V, Yeh LT, Girardet JL, Vernier JM, Raney AK, Pinkerton AB.
Abstract : SAR studies on the quinolone carboxylic acid class of HIV-1 integrase inhibitors focused on improving the metabolic stability and led to the discovery of 27 and 38.
|
Inhibition of HIV-1 integrase after 1 hr by ELISA
|
Human immunodeficiency virus 1
|
4.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : HIV-1 integrase strand-transfer inhibitors: design, synthesis and molecular modeling investigation.
Year : 2011
Volume : 46
Issue : 2
First Page : 756
Last Page : 764
Authors : De Luca L, De Grazia S, Ferro S, Gitto R, Christ F, Debyser Z, Chimirri A.
Abstract : This study is focused on a new series of benzylindole derivatives with various substituents at the benzene-fused ring, suggested by our 3D pharmacophore model developed for HIV-1 integrase inhibitors (INIs). All synthesized compounds proved to be active in the nanomolar range (6-35 nM) on the strand-transfer step (ST). In particular, derivative 4-[1-(4-fluorobenzyl)-5,7-dimethoxy-1H-indol-3-yl]-2-hydroxy-4-oxobut-2-enoic acid (8e), presenting the highest best-fit value on pharmacophore model, showed a potency comparable to that of clinical INSTIs GS 9137 (1) and MK-0518 (2). The binding mode of our molecules has been investigated using the recently published crystal structure of the complex of full-length integrase from the prototype foamy virus in complex with its cognate DNA (PFV-IN/DNA). The results highlighted the ability of derivative 8e to assume the same binding mode of MK-0518 and GS 9137.
|
Antiviral activity against HIV1 3B infected in human MT4 cells assessed as inhibition of virus-induced cytopathic effect by MTT assay
|
Human immunodeficiency virus 1
|
0.8
nM
|
|
Journal : Eur. J. Med. Chem.
Title : HIV-1 integrase strand-transfer inhibitors: design, synthesis and molecular modeling investigation.
Year : 2011
Volume : 46
Issue : 2
First Page : 756
Last Page : 764
Authors : De Luca L, De Grazia S, Ferro S, Gitto R, Christ F, Debyser Z, Chimirri A.
Abstract : This study is focused on a new series of benzylindole derivatives with various substituents at the benzene-fused ring, suggested by our 3D pharmacophore model developed for HIV-1 integrase inhibitors (INIs). All synthesized compounds proved to be active in the nanomolar range (6-35 nM) on the strand-transfer step (ST). In particular, derivative 4-[1-(4-fluorobenzyl)-5,7-dimethoxy-1H-indol-3-yl]-2-hydroxy-4-oxobut-2-enoic acid (8e), presenting the highest best-fit value on pharmacophore model, showed a potency comparable to that of clinical INSTIs GS 9137 (1) and MK-0518 (2). The binding mode of our molecules has been investigated using the recently published crystal structure of the complex of full-length integrase from the prototype foamy virus in complex with its cognate DNA (PFV-IN/DNA). The results highlighted the ability of derivative 8e to assume the same binding mode of MK-0518 and GS 9137.
|
Inhibition of Human immunodeficiency virus 1 integrase
|
Human immunodeficiency virus 1
|
3.8
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.
|
Inhibition of Human immunodeficiency virus 1 integrase strand transfer activity
|
Human immunodeficiency virus 1
|
15.0
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 Human immunodeficiency virus 1 3B infected in human MT4 cells assessed as inhibition of viral replication
|
Human immunodeficiency virus 1
|
0.83
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 Human immunodeficiency virus 1 3B infected in human MT4 cells assessed as inhibition of virus induced cytopathic effect
|
Human immunodeficiency virus 1
|
11.6
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Secondary integrase resistance mutations found in HIV-1 minority quasispecies in integrase therapy-naive patients have little or no effect on susceptibility to integrase inhibitors.
Year : 2010
Volume : 54
Issue : 9
First Page : 3938
Last Page : 3948
Authors : Ceccherini-Silberstein F, Van Baelen K, Armenia D, Trignetti M, Rondelez E, Fabeni L, Scopelliti F, Pollicita M, Van Wesenbeeck L, Van Eygen V, Dori L, Sarmati L, Aquaro S, Palamara G, Andreoni M, Stuyver LJ, Perno CF.
Abstract : The goal of this study was to explore the presence of integrase strand transfer inhibitor (InSTI) resistance mutations in HIV-1 quasispecies present in InSTI-naïve patients and to evaluate their in vitro effects on phenotypic susceptibility to InSTIs and their replication capacities. The RT-RNase H-IN region was PCR amplified from plasma viral RNA obtained from 49 HIV-1 subtype B-infected patients (21 drug naïve and 28 failing highly active antiretroviral therapy [HAART] not containing InSTIs) and recombined with an HXB2-based backbone with RT and IN deleted. Recombinant viruses were tested against raltegravir and elvitegravir and for replication capacity. Three-hundred forty-four recombinant viruses from 49 patients were successfully analyzed both phenotypically and genotypically. The majority of clones were not phenotypically resistant to InSTIs: 0/344 clones showed raltegravir resistance, and only 3 (0.87%) showed low-level elvitegravir resistance. No primary resistance mutations for raltegravir and elvitegravir were found as major or minor species. The majority of secondary mutations were also absent or rarely present. Secondary mutations, such as T97A and G140S, found rarely and only as minority quasispecies, were present in the elvitegravir-resistant clones. A novel mutation, E92G, although rarely found in minority quasispecies, showed elvitegravir resistance. Preexisting genotypic and phenotypic raltegravir resistance was extremely rare in InSTI-naïve patients and confined to only a restricted minority of secondary variants. Overall, these results, together with others based on population and ultradeep sequencing, suggest that at this point IN genotyping in all patients before raltegravir treatment may not be cost-effective and should not be recommended until evidence of transmitted drug resistance to InSTIs or the clinical relevance of IN minor variants/polymorphisms is determined.
|
Inhibition of strand transfer activity of Human immunodeficiency virus 1 Integrase using [3H]labeled target DNA as substrate after 45 mins by scintillation counting
|
Human immunodeficiency virus 1
|
6.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In Vitro antiretroviral properties of S/GSK1349572, a next-generation HIV integrase inhibitor.
Year : 2011
Volume : 55
Issue : 2
First Page : 813
Last Page : 821
Authors : Kobayashi M, Yoshinaga T, Seki T, Wakasa-Morimoto C, Brown KW, Ferris R, Foster SA, Hazen RJ, Miki S, Suyama-Kagitani A, Kawauchi-Miki S, Taishi T, Kawasuji T, Johns BA, Underwood MR, Garvey EP, Sato A, Fujiwara T.
Abstract : S/GSK1349572 is a next-generation HIV integrase (IN) inhibitor designed to deliver potent antiviral activity with a low-milligram once-daily dose requiring no pharmacokinetic (PK) booster. In addition, S/GSK1349572 demonstrates activity against clinically relevant IN mutant viruses and has potential for a high genetic barrier to resistance. S/GSK1349572 is a two-metal-binding HIV integrase strand transfer inhibitor whose mechanism of action was established through in vitro integrase enzyme assays, resistance passage experiments, activity against viral strains resistant to other classes of anti-HIV agents, and mechanistic cellular assays. In a variety of cellular antiviral assays, S/GSK1349572 inhibited HIV replication with low-nanomolar or subnanomolar potency and with a selectivity index of 9,400. The protein-adjusted half-maximal effective concentration (PA-EC(50)) extrapolated to 100% human serum was 38 nM. When virus was passaged in the presence of S/GSK1349572, highly resistant mutants were not selected, but mutations that effected a low fold change (FC) in the EC(50) (up to 4.1 fold) were identified in the vicinity of the integrase active site. S/GSK1349572 demonstrated activity against site-directed molecular clones containing the raltegravir-resistant signature mutations Y143R, Q148K, N155H, and G140S/Q148H (FCs, 1.4, 1.1, 1.2, and 2.6, respectively), while these mutants led to a high FC in the EC(50) of raltegravir (11- to >130-fold). Either additive or synergistic effects were observed when S/GSK1349572 was tested in combination with representative approved antiretroviral agents; no antagonistic effects were seen. These findings demonstrate that S/GSK1349572 would be classified as a next-generation drug in the integrase inhibitor class, with a resistance profile markedly different from that of first-generation integrase inhibitors.
|
Antiviral activity against Human immunodeficiency virus 1 Bal infected in human PBMC assessed as incorporation of [methly-3H]dTTP to viral DNA after 7 days by reverse transcriptase activity
|
Human immunodeficiency virus 1
|
2.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In Vitro antiretroviral properties of S/GSK1349572, a next-generation HIV integrase inhibitor.
Year : 2011
Volume : 55
Issue : 2
First Page : 813
Last Page : 821
Authors : Kobayashi M, Yoshinaga T, Seki T, Wakasa-Morimoto C, Brown KW, Ferris R, Foster SA, Hazen RJ, Miki S, Suyama-Kagitani A, Kawauchi-Miki S, Taishi T, Kawasuji T, Johns BA, Underwood MR, Garvey EP, Sato A, Fujiwara T.
Abstract : S/GSK1349572 is a next-generation HIV integrase (IN) inhibitor designed to deliver potent antiviral activity with a low-milligram once-daily dose requiring no pharmacokinetic (PK) booster. In addition, S/GSK1349572 demonstrates activity against clinically relevant IN mutant viruses and has potential for a high genetic barrier to resistance. S/GSK1349572 is a two-metal-binding HIV integrase strand transfer inhibitor whose mechanism of action was established through in vitro integrase enzyme assays, resistance passage experiments, activity against viral strains resistant to other classes of anti-HIV agents, and mechanistic cellular assays. In a variety of cellular antiviral assays, S/GSK1349572 inhibited HIV replication with low-nanomolar or subnanomolar potency and with a selectivity index of 9,400. The protein-adjusted half-maximal effective concentration (PA-EC(50)) extrapolated to 100% human serum was 38 nM. When virus was passaged in the presence of S/GSK1349572, highly resistant mutants were not selected, but mutations that effected a low fold change (FC) in the EC(50) (up to 4.1 fold) were identified in the vicinity of the integrase active site. S/GSK1349572 demonstrated activity against site-directed molecular clones containing the raltegravir-resistant signature mutations Y143R, Q148K, N155H, and G140S/Q148H (FCs, 1.4, 1.1, 1.2, and 2.6, respectively), while these mutants led to a high FC in the EC(50) of raltegravir (11- to >130-fold). Either additive or synergistic effects were observed when S/GSK1349572 was tested in combination with representative approved antiretroviral agents; no antagonistic effects were seen. These findings demonstrate that S/GSK1349572 would be classified as a next-generation drug in the integrase inhibitor class, with a resistance profile markedly different from that of first-generation integrase inhibitors.
|
Antiviral activity against Human immunodeficiency virus 1 Bal infected in human PBMC assessed as incorporation of [methly-3H]dTTP to viral DNA after 7 days by reverse transcriptase activity in presence of 20% human serum albumin
|
Human immunodeficiency virus 1
|
20.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In Vitro antiretroviral properties of S/GSK1349572, a next-generation HIV integrase inhibitor.
Year : 2011
Volume : 55
Issue : 2
First Page : 813
Last Page : 821
Authors : Kobayashi M, Yoshinaga T, Seki T, Wakasa-Morimoto C, Brown KW, Ferris R, Foster SA, Hazen RJ, Miki S, Suyama-Kagitani A, Kawauchi-Miki S, Taishi T, Kawasuji T, Johns BA, Underwood MR, Garvey EP, Sato A, Fujiwara T.
Abstract : S/GSK1349572 is a next-generation HIV integrase (IN) inhibitor designed to deliver potent antiviral activity with a low-milligram once-daily dose requiring no pharmacokinetic (PK) booster. In addition, S/GSK1349572 demonstrates activity against clinically relevant IN mutant viruses and has potential for a high genetic barrier to resistance. S/GSK1349572 is a two-metal-binding HIV integrase strand transfer inhibitor whose mechanism of action was established through in vitro integrase enzyme assays, resistance passage experiments, activity against viral strains resistant to other classes of anti-HIV agents, and mechanistic cellular assays. In a variety of cellular antiviral assays, S/GSK1349572 inhibited HIV replication with low-nanomolar or subnanomolar potency and with a selectivity index of 9,400. The protein-adjusted half-maximal effective concentration (PA-EC(50)) extrapolated to 100% human serum was 38 nM. When virus was passaged in the presence of S/GSK1349572, highly resistant mutants were not selected, but mutations that effected a low fold change (FC) in the EC(50) (up to 4.1 fold) were identified in the vicinity of the integrase active site. S/GSK1349572 demonstrated activity against site-directed molecular clones containing the raltegravir-resistant signature mutations Y143R, Q148K, N155H, and G140S/Q148H (FCs, 1.4, 1.1, 1.2, and 2.6, respectively), while these mutants led to a high FC in the EC(50) of raltegravir (11- to >130-fold). Either additive or synergistic effects were observed when S/GSK1349572 was tested in combination with representative approved antiretroviral agents; no antagonistic effects were seen. These findings demonstrate that S/GSK1349572 would be classified as a next-generation drug in the integrase inhibitor class, with a resistance profile markedly different from that of first-generation integrase inhibitors.
|
Antiviral activity against HIV1 NL4-3.Luc assessed as infectivity using human MDM pretreated for 24 hrs followed by exposed to virus after compound washout measured after 2 to 3 days by luciferase assay
|
Human immunodeficiency virus 1
|
25.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Identification and characterization of persistent intracellular human immunodeficiency virus type 1 integrase strand transfer inhibitor activity.
Year : 2011
Volume : 55
Issue : 1
First Page : 42
Last Page : 49
Authors : Koh Y, Haim H, Engelman A.
Abstract : Pharmacokinetic and pharmacodynamic considerations significantly impact infectious disease treatment options. One aspect of pharmacodynamics is the postantibiotic effect, classically defined as delayed bacterial growth after antibiotic removal. The same principle can apply to antiviral drugs. For example, significant delays in human immunodeficiency virus type 1 (HIV-1) replication can be observed after nucleoside/nucleotide reverse transcriptase inhibitor (N/NtRTI) removal from culture medium, because these prodrugs must be anabolized into active, phosphorylated forms once internalized into cells. A relatively new class of anti-HIV-1 drugs is the integrase strand transfer inhibitors (INSTIs), and the INSTIs raltegravir (RAL) and elvitegravir (EVG) were tested here alongside positive N/NtRTI controls tenofovir disoproxil fumarate (TDF) and azidothymidine (AZT), as well as the nonnucleoside reverse transcriptase inhibitor negative control nevirapine (NVP), to assess potential postantiviral effects. Transformed and primary CD4-positive cells pretreated with INSTIs significantly resisted subsequent challenge by HIV-1, revealing the following hierarchy of persistent intracellular drug strength: TDF > EVG ∼ AZT > RAL > NVP. A modified time-of-addition assay was moreover developed to assess residual drug activity levels. Approximately 0.8% of RAL and 2% of initial EVG and TDF 1-h pulse drug levels persisted during the acute phase of HIV-1 infection. EVG furthermore displayed significant virucidal activity. Although there is no reason to suspect obligate intracellular modification, this study nevertheless defines significant intracellular persistence of prototype INSTIs. Ongoing second-generation formulations should therefore consider the potential for significant postantiviral effects among this drug class. Combined intracellular persistence and virucidal activities suggest potential pre-exposure prophylaxis applications for EVG.
|
Antiviral activity against HIV1 NL4-3.Luc assessed as infectivity using human PBMC pretreated for 24 hrs followed by exposed to virus after compound washout measured after 2 to 3 days by luciferase assay
|
Human immunodeficiency virus 1
|
36.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Identification and characterization of persistent intracellular human immunodeficiency virus type 1 integrase strand transfer inhibitor activity.
Year : 2011
Volume : 55
Issue : 1
First Page : 42
Last Page : 49
Authors : Koh Y, Haim H, Engelman A.
Abstract : Pharmacokinetic and pharmacodynamic considerations significantly impact infectious disease treatment options. One aspect of pharmacodynamics is the postantibiotic effect, classically defined as delayed bacterial growth after antibiotic removal. The same principle can apply to antiviral drugs. For example, significant delays in human immunodeficiency virus type 1 (HIV-1) replication can be observed after nucleoside/nucleotide reverse transcriptase inhibitor (N/NtRTI) removal from culture medium, because these prodrugs must be anabolized into active, phosphorylated forms once internalized into cells. A relatively new class of anti-HIV-1 drugs is the integrase strand transfer inhibitors (INSTIs), and the INSTIs raltegravir (RAL) and elvitegravir (EVG) were tested here alongside positive N/NtRTI controls tenofovir disoproxil fumarate (TDF) and azidothymidine (AZT), as well as the nonnucleoside reverse transcriptase inhibitor negative control nevirapine (NVP), to assess potential postantiviral effects. Transformed and primary CD4-positive cells pretreated with INSTIs significantly resisted subsequent challenge by HIV-1, revealing the following hierarchy of persistent intracellular drug strength: TDF > EVG ∼ AZT > RAL > NVP. A modified time-of-addition assay was moreover developed to assess residual drug activity levels. Approximately 0.8% of RAL and 2% of initial EVG and TDF 1-h pulse drug levels persisted during the acute phase of HIV-1 infection. EVG furthermore displayed significant virucidal activity. Although there is no reason to suspect obligate intracellular modification, this study nevertheless defines significant intracellular persistence of prototype INSTIs. Ongoing second-generation formulations should therefore consider the potential for significant postantiviral effects among this drug class. Combined intracellular persistence and virucidal activities suggest potential pre-exposure prophylaxis applications for EVG.
|
Antiviral activity against single-round HIV1 NLX.Lux-R harboring inactivating mutations in env, vpr and carries firefly luciferase gene in place of nef infected in human HeLa-T4 cells assessed as luciferase activity after 48 hrs by exogenous RT assay
|
Human immunodeficiency virus 1
|
30.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Identification and characterization of persistent intracellular human immunodeficiency virus type 1 integrase strand transfer inhibitor activity.
Year : 2011
Volume : 55
Issue : 1
First Page : 42
Last Page : 49
Authors : Koh Y, Haim H, Engelman A.
Abstract : Pharmacokinetic and pharmacodynamic considerations significantly impact infectious disease treatment options. One aspect of pharmacodynamics is the postantibiotic effect, classically defined as delayed bacterial growth after antibiotic removal. The same principle can apply to antiviral drugs. For example, significant delays in human immunodeficiency virus type 1 (HIV-1) replication can be observed after nucleoside/nucleotide reverse transcriptase inhibitor (N/NtRTI) removal from culture medium, because these prodrugs must be anabolized into active, phosphorylated forms once internalized into cells. A relatively new class of anti-HIV-1 drugs is the integrase strand transfer inhibitors (INSTIs), and the INSTIs raltegravir (RAL) and elvitegravir (EVG) were tested here alongside positive N/NtRTI controls tenofovir disoproxil fumarate (TDF) and azidothymidine (AZT), as well as the nonnucleoside reverse transcriptase inhibitor negative control nevirapine (NVP), to assess potential postantiviral effects. Transformed and primary CD4-positive cells pretreated with INSTIs significantly resisted subsequent challenge by HIV-1, revealing the following hierarchy of persistent intracellular drug strength: TDF > EVG ∼ AZT > RAL > NVP. A modified time-of-addition assay was moreover developed to assess residual drug activity levels. Approximately 0.8% of RAL and 2% of initial EVG and TDF 1-h pulse drug levels persisted during the acute phase of HIV-1 infection. EVG furthermore displayed significant virucidal activity. Although there is no reason to suspect obligate intracellular modification, this study nevertheless defines significant intracellular persistence of prototype INSTIs. Ongoing second-generation formulations should therefore consider the potential for significant postantiviral effects among this drug class. Combined intracellular persistence and virucidal activities suggest potential pre-exposure prophylaxis applications for EVG.
|
Antiviral activity against single-round HIV1 NLX.Lux-R harboring inactivating mutations in env, vpr and carries firefly luciferase gene in place of nef assessed as level of infection using human HeLaT4 cells pretreated for 24 hrs followed by exposed to virus immediately after 3 times compound washout
|
Human immunodeficiency virus 1
|
60.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Identification and characterization of persistent intracellular human immunodeficiency virus type 1 integrase strand transfer inhibitor activity.
Year : 2011
Volume : 55
Issue : 1
First Page : 42
Last Page : 49
Authors : Koh Y, Haim H, Engelman A.
Abstract : Pharmacokinetic and pharmacodynamic considerations significantly impact infectious disease treatment options. One aspect of pharmacodynamics is the postantibiotic effect, classically defined as delayed bacterial growth after antibiotic removal. The same principle can apply to antiviral drugs. For example, significant delays in human immunodeficiency virus type 1 (HIV-1) replication can be observed after nucleoside/nucleotide reverse transcriptase inhibitor (N/NtRTI) removal from culture medium, because these prodrugs must be anabolized into active, phosphorylated forms once internalized into cells. A relatively new class of anti-HIV-1 drugs is the integrase strand transfer inhibitors (INSTIs), and the INSTIs raltegravir (RAL) and elvitegravir (EVG) were tested here alongside positive N/NtRTI controls tenofovir disoproxil fumarate (TDF) and azidothymidine (AZT), as well as the nonnucleoside reverse transcriptase inhibitor negative control nevirapine (NVP), to assess potential postantiviral effects. Transformed and primary CD4-positive cells pretreated with INSTIs significantly resisted subsequent challenge by HIV-1, revealing the following hierarchy of persistent intracellular drug strength: TDF > EVG ∼ AZT > RAL > NVP. A modified time-of-addition assay was moreover developed to assess residual drug activity levels. Approximately 0.8% of RAL and 2% of initial EVG and TDF 1-h pulse drug levels persisted during the acute phase of HIV-1 infection. EVG furthermore displayed significant virucidal activity. Although there is no reason to suspect obligate intracellular modification, this study nevertheless defines significant intracellular persistence of prototype INSTIs. Ongoing second-generation formulations should therefore consider the potential for significant postantiviral effects among this drug class. Combined intracellular persistence and virucidal activities suggest potential pre-exposure prophylaxis applications for EVG.
|
Antiviral activity against HIV1 NL4-3.Luc in human PBMC assessed as infectivity treated for 24 hrs by luciferase assay
|
Human immunodeficiency virus 1
|
0.3
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Identification and characterization of persistent intracellular human immunodeficiency virus type 1 integrase strand transfer inhibitor activity.
Year : 2011
Volume : 55
Issue : 1
First Page : 42
Last Page : 49
Authors : Koh Y, Haim H, Engelman A.
Abstract : Pharmacokinetic and pharmacodynamic considerations significantly impact infectious disease treatment options. One aspect of pharmacodynamics is the postantibiotic effect, classically defined as delayed bacterial growth after antibiotic removal. The same principle can apply to antiviral drugs. For example, significant delays in human immunodeficiency virus type 1 (HIV-1) replication can be observed after nucleoside/nucleotide reverse transcriptase inhibitor (N/NtRTI) removal from culture medium, because these prodrugs must be anabolized into active, phosphorylated forms once internalized into cells. A relatively new class of anti-HIV-1 drugs is the integrase strand transfer inhibitors (INSTIs), and the INSTIs raltegravir (RAL) and elvitegravir (EVG) were tested here alongside positive N/NtRTI controls tenofovir disoproxil fumarate (TDF) and azidothymidine (AZT), as well as the nonnucleoside reverse transcriptase inhibitor negative control nevirapine (NVP), to assess potential postantiviral effects. Transformed and primary CD4-positive cells pretreated with INSTIs significantly resisted subsequent challenge by HIV-1, revealing the following hierarchy of persistent intracellular drug strength: TDF > EVG ∼ AZT > RAL > NVP. A modified time-of-addition assay was moreover developed to assess residual drug activity levels. Approximately 0.8% of RAL and 2% of initial EVG and TDF 1-h pulse drug levels persisted during the acute phase of HIV-1 infection. EVG furthermore displayed significant virucidal activity. Although there is no reason to suspect obligate intracellular modification, this study nevertheless defines significant intracellular persistence of prototype INSTIs. Ongoing second-generation formulations should therefore consider the potential for significant postantiviral effects among this drug class. Combined intracellular persistence and virucidal activities suggest potential pre-exposure prophylaxis applications for EVG.
|
Antiviral activity against HIV1 NL4-3.Luc in human MDM assessed as infectivity treated for 24 hrs by luciferase assay
|
Human immunodeficiency virus 1
|
0.5
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Identification and characterization of persistent intracellular human immunodeficiency virus type 1 integrase strand transfer inhibitor activity.
Year : 2011
Volume : 55
Issue : 1
First Page : 42
Last Page : 49
Authors : Koh Y, Haim H, Engelman A.
Abstract : Pharmacokinetic and pharmacodynamic considerations significantly impact infectious disease treatment options. One aspect of pharmacodynamics is the postantibiotic effect, classically defined as delayed bacterial growth after antibiotic removal. The same principle can apply to antiviral drugs. For example, significant delays in human immunodeficiency virus type 1 (HIV-1) replication can be observed after nucleoside/nucleotide reverse transcriptase inhibitor (N/NtRTI) removal from culture medium, because these prodrugs must be anabolized into active, phosphorylated forms once internalized into cells. A relatively new class of anti-HIV-1 drugs is the integrase strand transfer inhibitors (INSTIs), and the INSTIs raltegravir (RAL) and elvitegravir (EVG) were tested here alongside positive N/NtRTI controls tenofovir disoproxil fumarate (TDF) and azidothymidine (AZT), as well as the nonnucleoside reverse transcriptase inhibitor negative control nevirapine (NVP), to assess potential postantiviral effects. Transformed and primary CD4-positive cells pretreated with INSTIs significantly resisted subsequent challenge by HIV-1, revealing the following hierarchy of persistent intracellular drug strength: TDF > EVG ∼ AZT > RAL > NVP. A modified time-of-addition assay was moreover developed to assess residual drug activity levels. Approximately 0.8% of RAL and 2% of initial EVG and TDF 1-h pulse drug levels persisted during the acute phase of HIV-1 infection. EVG furthermore displayed significant virucidal activity. Although there is no reason to suspect obligate intracellular modification, this study nevertheless defines significant intracellular persistence of prototype INSTIs. Ongoing second-generation formulations should therefore consider the potential for significant postantiviral effects among this drug class. Combined intracellular persistence and virucidal activities suggest potential pre-exposure prophylaxis applications for EVG.
|
Antiviral activity against HIV1 LAI 3B infected in human C8166 cells assessed as protection against virus-induced cytopathic effect by MTT assay
|
Human immunodeficiency virus 1
|
0.21
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Structural modifications of quinolone-3-carboxylic acids with anti-HIV activity.
Year : 2011
Volume : 19
Issue : 16
First Page : 5039
Last Page : 5045
Authors : He QQ, Gu SX, Liu J, Wu HQ, Zhang X, Yang LM, Zheng YT, Chen FE.
Abstract : A series of new quinolone-3-carboxylic acids featuring a hydroxyl group at C-5 position were synthesized and evaluated for their in vitro activity against HIV in C8166 cell culture. All the compounds showed anti-HIV-1 activity with low micromolar to submicromolar EC(50) values. The most active compound 2k exhibited activity against wild-type HIV-1 with an EC(50) value of 0.13 μΜ. Preliminary structure-activity relationship of the newly synthesized quinolone analogues was also investigated. Further docking study revealed that the anti-HIV activity of these compounds might involve a two-metal chelating mechanism.
|
Antiviral activity against wild type HIV1 LAI-3B infected in human C8166 cells assessed as inhibition of virus-induced cytopathic effect by MTT assay
|
Human immunodeficiency virus 1
|
0.21
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and biological evaluation of HQCAs with aryl or benzyl substituents on N-1 position as potential HIV-1 integrase inhibitors.
Year : 2011
Volume : 19
Issue : 18
First Page : 5553
Last Page : 5558
Authors : He QQ, Zhang X, Wu HQ, Gu SX, Ma XD, Yang LM, Zheng YT, Chen FE.
Abstract : A series of new 5-hydroxylquinolone-3-carboxylic acids (HQCAs) with various aryl or benzyl substituents on N-1 position were synthesized and evaluated for their anti-HIV activity in C8166 cell culture. Most of the target compounds displayed activity against wide-type HIV-1 in the low micromolar range in infected C8166 cells. The most active compound 5 g exhibited activity against wild-type HIV-1 and HIV-1 mutant virus A17 with an EC(50) value of 3.17 and 17.88 μM, respectively. The biological results and the docking study revealed that the substitution pattern on N-1 position of the quinolone core might contribute to physicochemical properties of HQCAs and resulted in great influence on their antiviral potency.
|
Antiviral activity against HIV1 A17 harboring reverse transcriptase Y181C mutant infected in human C8166 cells assessed as inhibition of virus-induced cytopathic effect by MTT assay
|
Human immunodeficiency virus 1
|
1.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and biological evaluation of HQCAs with aryl or benzyl substituents on N-1 position as potential HIV-1 integrase inhibitors.
Year : 2011
Volume : 19
Issue : 18
First Page : 5553
Last Page : 5558
Authors : He QQ, Zhang X, Wu HQ, Gu SX, Ma XD, Yang LM, Zheng YT, Chen FE.
Abstract : A series of new 5-hydroxylquinolone-3-carboxylic acids (HQCAs) with various aryl or benzyl substituents on N-1 position were synthesized and evaluated for their anti-HIV activity in C8166 cell culture. Most of the target compounds displayed activity against wide-type HIV-1 in the low micromolar range in infected C8166 cells. The most active compound 5 g exhibited activity against wild-type HIV-1 and HIV-1 mutant virus A17 with an EC(50) value of 3.17 and 17.88 μM, respectively. The biological results and the docking study revealed that the substitution pattern on N-1 position of the quinolone core might contribute to physicochemical properties of HQCAs and resulted in great influence on their antiviral potency.
|
Inhibition of wild type HIV1 3B infected in human MT4 cells using cells pre-incubated with compound for 1 hr measured 4 days post viral infection by MTT assay
|
Human immunodeficiency virus 1
|
1.3
nM
|
|
Journal : J. Med. Chem.
Title : Carbamoyl pyridone HIV-1 integrase inhibitors. 1. Molecular design and establishment of an advanced two-metal binding pharmacophore.
Year : 2012
Volume : 55
Issue : 20
First Page : 8735
Last Page : 8744
Authors : Kawasuji T, Johns BA, Yoshida H, Taishi T, Taoda Y, Murai H, Kiyama R, Fuji M, Yoshinaga T, Seki T, Kobayashi M, Sato A, Fujiwara T.
Abstract : Our group has focused on expanding the scope of a two-metal binding pharmacophore concept to explore HIV-1 integrase inhibitors through medicinal chemistry efforts to design novel scaffolds which allow for improvement of pharmacokinetic (PK) and resistance profiles. A novel chelating scaffold was rationally designed to effectively coordinate two magnesium cofactors and to extend an aromatic group into an optimal hydrophobic pharmacophore space. The new chemotype, consisting of a carbamoyl pyridone core unit, shows high inhibitory potency in both enzymatic and antiviral assay formats with low nM IC₅₀ and encouraging potency shift effects in the presence of relevant serum proteins. The new inhibitor design displayed a remarkable PK profile suggestive of once daily dosing without the need for a PK booster as demonstrated by robust drug concentrations at 24 h after oral dosing in rats, dogs, and cynomolgus monkeys.
|
Inhibition of wild type HIV1 3B infected in human MT4 cells using cells pre-incubated with compound for 1 hr measured 4 days post viral infection in presence of 20 mg/ml HSA by MTT assay
|
Human immunodeficiency virus 1
|
29.0
nM
|
|
Journal : J. Med. Chem.
Title : Carbamoyl pyridone HIV-1 integrase inhibitors. 1. Molecular design and establishment of an advanced two-metal binding pharmacophore.
Year : 2012
Volume : 55
Issue : 20
First Page : 8735
Last Page : 8744
Authors : Kawasuji T, Johns BA, Yoshida H, Taishi T, Taoda Y, Murai H, Kiyama R, Fuji M, Yoshinaga T, Seki T, Kobayashi M, Sato A, Fujiwara T.
Abstract : Our group has focused on expanding the scope of a two-metal binding pharmacophore concept to explore HIV-1 integrase inhibitors through medicinal chemistry efforts to design novel scaffolds which allow for improvement of pharmacokinetic (PK) and resistance profiles. A novel chelating scaffold was rationally designed to effectively coordinate two magnesium cofactors and to extend an aromatic group into an optimal hydrophobic pharmacophore space. The new chemotype, consisting of a carbamoyl pyridone core unit, shows high inhibitory potency in both enzymatic and antiviral assay formats with low nM IC₅₀ and encouraging potency shift effects in the presence of relevant serum proteins. The new inhibitor design displayed a remarkable PK profile suggestive of once daily dosing without the need for a PK booster as demonstrated by robust drug concentrations at 24 h after oral dosing in rats, dogs, and cynomolgus monkeys.
|
Inhibition of HIV1 integrase strand transfer activity by gel-based assay
|
Human immunodeficiency virus 1
|
28.0
nM
|
|
Journal : J. Med. Chem.
Title : Basic quinolinonyl diketo acid derivatives as inhibitors of HIV integrase and their activity against RNase H function of reverse transcriptase.
Year : 2014
Volume : 57
Issue : 8
First Page : 3223
Last Page : 3234
Authors : Costi R, Métifiot M, Chung S, Cuzzucoli Crucitti G, Maddali K, Pescatori L, Messore A, Madia VN, Pupo G, Scipione L, Tortorella S, Di Leva FS, Cosconati S, Marinelli L, Novellino E, Le Grice SF, Corona A, Pommier Y, Marchand C, Di Santo R.
Abstract : A series of antiviral basic quinolinonyl diketo acid derivatives were developed as inhibitors of HIV-1 IN. Compounds 12d,f,i inhibited HIV-1 IN with IC50 values below 100 nM for strand transfer and showed a 2 order of magnitude selectivity over 3'-processing. These strand transfer selective inhibitors also inhibited HIV-1 RNase H with low micromolar potencies. Molecular modeling studies based on both the HIV-1 IN and RNase H catalytic core domains provided new structural insights for the future development of these compounds as dual HIV-1 IN and RNase H inhibitors.
|
Antiviral activity against HIV1 3B infected in human HeLa cells expressing CD4-LTR-beta-gal assessed as inhibition of viral replication after 3 days by reporter gene assay
|
Human immunodeficiency virus 1
|
14.2
nM
|
|
Journal : J. Med. Chem.
Title : Basic quinolinonyl diketo acid derivatives as inhibitors of HIV integrase and their activity against RNase H function of reverse transcriptase.
Year : 2014
Volume : 57
Issue : 8
First Page : 3223
Last Page : 3234
Authors : Costi R, Métifiot M, Chung S, Cuzzucoli Crucitti G, Maddali K, Pescatori L, Messore A, Madia VN, Pupo G, Scipione L, Tortorella S, Di Leva FS, Cosconati S, Marinelli L, Novellino E, Le Grice SF, Corona A, Pommier Y, Marchand C, Di Santo R.
Abstract : A series of antiviral basic quinolinonyl diketo acid derivatives were developed as inhibitors of HIV-1 IN. Compounds 12d,f,i inhibited HIV-1 IN with IC50 values below 100 nM for strand transfer and showed a 2 order of magnitude selectivity over 3'-processing. These strand transfer selective inhibitors also inhibited HIV-1 RNase H with low micromolar potencies. Molecular modeling studies based on both the HIV-1 IN and RNase H catalytic core domains provided new structural insights for the future development of these compounds as dual HIV-1 IN and RNase H inhibitors.
|
Inhibition of HIV-1 integrase assessed as inhibition of strand transfer activity using 32P-labeled DNA as substrate after 1 hr by gel-based assay in presence of Mg2+
|
Human immunodeficiency virus 1
|
28.0
nM
|
|
Journal : J. Med. Chem.
Title : N-Substituted Quinolinonyl Diketo Acid Derivatives as HIV Integrase Strand Transfer Inhibitors and Their Activity against RNase H Function of Reverse Transcriptase.
Year : 2015
Volume : 58
Issue : 11
First Page : 4610
Last Page : 4623
Authors : Pescatori L, Métifiot M, Chung S, Masoaka T, Cuzzucoli Crucitti G, Messore A, Pupo G, Madia VN, Saccoliti F, Scipione L, Tortorella S, Di Leva FS, Cosconati S, Marinelli L, Novellino E, Le Grice SF, Pommier Y, Marchand C, Costi R, Di Santo R.
Abstract : Bifunctional quinolinonyl DKA derivatives were first described as nonselective inhibitors of 3'-processing (3'-P) and strand transfer (ST) functions of HIV-1 integrase (IN), while 7-aminosubstituted quinolinonyl derivatives were proven IN strand transfer inhibitors (INSTIs) that also displayed activity against ribonuclease H (RNase H). In this study, we describe the design, synthesis, and biological evaluation of new quinolinonyl diketo acid (DKA) derivatives characterized by variously substituted alkylating groups on the nitrogen atom of the quinolinone ring. Removal of the second DKA branch of bifunctional DKAs, and the amino group in position 7 of quinolinone ring combined with a fine-tuning of the substituents on the benzyl group in position 1 of the quinolinone, increased selectivity for IN ST activity. In vitro, the most potent compound was 11j (IC50 = 10 nM), while the most active compounds against HIV infected cells were ester derivatives 10j and 10l. In general, the activity against RNase H was negligible, with only a few compounds active at concentrations higher than 10 μM. The binding mode of the most potent IN inhibitor 11j within the IN catalytic core domain (CCD) is described as well as its binding mode within the RNase H catalytic site to rationalize its selectivity.
|
Antiviral activity against HIV-1 3B infected in human HeLa-CD4-LTR-beta-gal cells assessed as inhibition of viral replication by SpectraMax GEMINI-XS plate reader analysis
|
Human immunodeficiency virus 1
|
14.2
nM
|
|
Journal : J. Med. Chem.
Title : N-Substituted Quinolinonyl Diketo Acid Derivatives as HIV Integrase Strand Transfer Inhibitors and Their Activity against RNase H Function of Reverse Transcriptase.
Year : 2015
Volume : 58
Issue : 11
First Page : 4610
Last Page : 4623
Authors : Pescatori L, Métifiot M, Chung S, Masoaka T, Cuzzucoli Crucitti G, Messore A, Pupo G, Madia VN, Saccoliti F, Scipione L, Tortorella S, Di Leva FS, Cosconati S, Marinelli L, Novellino E, Le Grice SF, Pommier Y, Marchand C, Costi R, Di Santo R.
Abstract : Bifunctional quinolinonyl DKA derivatives were first described as nonselective inhibitors of 3'-processing (3'-P) and strand transfer (ST) functions of HIV-1 integrase (IN), while 7-aminosubstituted quinolinonyl derivatives were proven IN strand transfer inhibitors (INSTIs) that also displayed activity against ribonuclease H (RNase H). In this study, we describe the design, synthesis, and biological evaluation of new quinolinonyl diketo acid (DKA) derivatives characterized by variously substituted alkylating groups on the nitrogen atom of the quinolinone ring. Removal of the second DKA branch of bifunctional DKAs, and the amino group in position 7 of quinolinone ring combined with a fine-tuning of the substituents on the benzyl group in position 1 of the quinolinone, increased selectivity for IN ST activity. In vitro, the most potent compound was 11j (IC50 = 10 nM), while the most active compounds against HIV infected cells were ester derivatives 10j and 10l. In general, the activity against RNase H was negligible, with only a few compounds active at concentrations higher than 10 μM. The binding mode of the most potent IN inhibitor 11j within the IN catalytic core domain (CCD) is described as well as its binding mode within the RNase H catalytic site to rationalize its selectivity.
|
Antiviral activity against wild-type HIV1 3B infected in human MT4 cells assessed as protection of cells from virus-induced cytopathic after 5 days by MTT assay
|
Human immunodeficiency virus 1
|
3.1
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Anti-HIV diarylpyrimidine-quinolone hybrids and their mode of action.
Year : 2015
Volume : 23
Issue : 13
First Page : 3860
Last Page : 3868
Authors : Mao TQ, He QQ, Wan ZY, Chen WX, Chen FE, Tang GF, De Clercq E, Daelemans D, Pannecouque C.
Abstract : A molecular hybridization approach is a powerful tool in the design of new molecules with improved affinity and efficacy. In this context, a series of diarylpyrimidine-quinolone hybrids were synthesized and evaluated against both wt HIV-1 and mutant viral strains. The most active hybrid 5a displayed an EC50 value of 0.28±0.07μM against HIV-1 IIIB. A couple of enzyme-based assays clearly pinpoint a RT-targeted mechanism of action. Docking studies revealed that these hybrids could be well located in the NNIBP of HIV-1 RT despite the bulky and polar properties of a quinolone 3-carboxylic acid moiety in the molecules.
|
Antiviral activity against HIV1 harboring K103N/Y181C double mutant infected in human MT4 cells assessed as protection of cells from virus-induced cytopathic after 5 days by MTT assay
|
Human immunodeficiency virus 1
|
2.2
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Anti-HIV diarylpyrimidine-quinolone hybrids and their mode of action.
Year : 2015
Volume : 23
Issue : 13
First Page : 3860
Last Page : 3868
Authors : Mao TQ, He QQ, Wan ZY, Chen WX, Chen FE, Tang GF, De Clercq E, Daelemans D, Pannecouque C.
Abstract : A molecular hybridization approach is a powerful tool in the design of new molecules with improved affinity and efficacy. In this context, a series of diarylpyrimidine-quinolone hybrids were synthesized and evaluated against both wt HIV-1 and mutant viral strains. The most active hybrid 5a displayed an EC50 value of 0.28±0.07μM against HIV-1 IIIB. A couple of enzyme-based assays clearly pinpoint a RT-targeted mechanism of action. Docking studies revealed that these hybrids could be well located in the NNIBP of HIV-1 RT despite the bulky and polar properties of a quinolone 3-carboxylic acid moiety in the molecules.
|
Inhibition of HIV1 integrase
|
Human immunodeficiency virus 1
|
1.8
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Anti-HIV diarylpyrimidine-quinolone hybrids and their mode of action.
Year : 2015
Volume : 23
Issue : 13
First Page : 3860
Last Page : 3868
Authors : Mao TQ, He QQ, Wan ZY, Chen WX, Chen FE, Tang GF, De Clercq E, Daelemans D, Pannecouque C.
Abstract : A molecular hybridization approach is a powerful tool in the design of new molecules with improved affinity and efficacy. In this context, a series of diarylpyrimidine-quinolone hybrids were synthesized and evaluated against both wt HIV-1 and mutant viral strains. The most active hybrid 5a displayed an EC50 value of 0.28±0.07μM against HIV-1 IIIB. A couple of enzyme-based assays clearly pinpoint a RT-targeted mechanism of action. Docking studies revealed that these hybrids could be well located in the NNIBP of HIV-1 RT despite the bulky and polar properties of a quinolone 3-carboxylic acid moiety in the molecules.
|
Antiviral activity against HIV1 3B infected in human MT4 cells assessed as inhibition of viral-induced cytopathic effect by MTT assay
|
Human immunodeficiency virus 1
|
2.3
nM
|
|
Journal : Bioorg Med Chem
Title : 1-Hydroxypyrido[2,3-d]pyrimidin-2(1H)-ones as novel selective HIV integrase inhibitors obtained via privileged substructure-based compound libraries.
Year : 2017
Volume : 25
Issue : 20
First Page : 5779
Last Page : 5789
Authors : Gao P, Zhang L, Sun L, Huang T, Tan J, Zhang J, Zhou Z, Zhao T, Menéndez-Arias L, Pannecouque C, Clercq E, Zhan P, Liu X.
Abstract : A small library containing 3-hydroxyquinazoline-2,4(1H,3H)-dione and 1-hydroxypyrido[2,3-d]pyrimidin-2(1H)-one scaffolds was obtained via the copper(I)-catalyzed azidealkyne cycloaddition (CuAAC) reaction and evaluated for their anti-HIV activity in MT-4 cells. Among the synthesized compounds, several 1-hydroxypyrido[2,3-d]pyrimidin-2(1H)-one derivatives showed remarkable anti-HIV potency with EC50 values ranging from 0.92 to 26.85µM. The most active one, IIA-2, also showed remarkable and selective potency against HIV type 1 integrase (IN). To the best of our knowledge, this is the first report showing that 1-hydroxypyrido[2,3-d]pyrimidin-2(1H)-ones are selective HIV IN inhibitors. Preliminary structure-activity relationship (SAR) studies suggested that the divalent metal ion chelators and the nature and position of substituents around the core are important for antiviral potency. Molecular modeling has been used to predict the binding site of the pyrido[2,3-d]pyrimidin-2(1H)-one core in HIV type 1 IN and suggestions are made for improvement of its inhibitory activity.
|
Antiviral activity against HIV2 ROD 3B infected in human MT4 cells assessed as inhibition of viral-induced cytopathic effect by MTT assay
|
Human immunodeficiency virus type 2 (ISOLATE ROD)
|
3.8
nM
|
|
Journal : Bioorg Med Chem
Title : 1-Hydroxypyrido[2,3-d]pyrimidin-2(1H)-ones as novel selective HIV integrase inhibitors obtained via privileged substructure-based compound libraries.
Year : 2017
Volume : 25
Issue : 20
First Page : 5779
Last Page : 5789
Authors : Gao P, Zhang L, Sun L, Huang T, Tan J, Zhang J, Zhou Z, Zhao T, Menéndez-Arias L, Pannecouque C, Clercq E, Zhan P, Liu X.
Abstract : A small library containing 3-hydroxyquinazoline-2,4(1H,3H)-dione and 1-hydroxypyrido[2,3-d]pyrimidin-2(1H)-one scaffolds was obtained via the copper(I)-catalyzed azidealkyne cycloaddition (CuAAC) reaction and evaluated for their anti-HIV activity in MT-4 cells. Among the synthesized compounds, several 1-hydroxypyrido[2,3-d]pyrimidin-2(1H)-one derivatives showed remarkable anti-HIV potency with EC50 values ranging from 0.92 to 26.85µM. The most active one, IIA-2, also showed remarkable and selective potency against HIV type 1 integrase (IN). To the best of our knowledge, this is the first report showing that 1-hydroxypyrido[2,3-d]pyrimidin-2(1H)-ones are selective HIV IN inhibitors. Preliminary structure-activity relationship (SAR) studies suggested that the divalent metal ion chelators and the nature and position of substituents around the core are important for antiviral potency. Molecular modeling has been used to predict the binding site of the pyrido[2,3-d]pyrimidin-2(1H)-one core in HIV type 1 IN and suggestions are made for improvement of its inhibitory activity.
|
Inhibition of HIV1 recombinant integrase strand transfer activity at 10 ug/ml using biotin-labeled double-stranded HIV-1 LTR U5 donor DNA substrate incubated for 5 mins after substrate addition for 30 mins by ELISA
|
Human immunodeficiency virus 1
|
97.8
%
|
|
Journal : Bioorg Med Chem
Title : 1-Hydroxypyrido[2,3-d]pyrimidin-2(1H)-ones as novel selective HIV integrase inhibitors obtained via privileged substructure-based compound libraries.
Year : 2017
Volume : 25
Issue : 20
First Page : 5779
Last Page : 5789
Authors : Gao P, Zhang L, Sun L, Huang T, Tan J, Zhang J, Zhou Z, Zhao T, Menéndez-Arias L, Pannecouque C, Clercq E, Zhan P, Liu X.
Abstract : A small library containing 3-hydroxyquinazoline-2,4(1H,3H)-dione and 1-hydroxypyrido[2,3-d]pyrimidin-2(1H)-one scaffolds was obtained via the copper(I)-catalyzed azidealkyne cycloaddition (CuAAC) reaction and evaluated for their anti-HIV activity in MT-4 cells. Among the synthesized compounds, several 1-hydroxypyrido[2,3-d]pyrimidin-2(1H)-one derivatives showed remarkable anti-HIV potency with EC50 values ranging from 0.92 to 26.85µM. The most active one, IIA-2, also showed remarkable and selective potency against HIV type 1 integrase (IN). To the best of our knowledge, this is the first report showing that 1-hydroxypyrido[2,3-d]pyrimidin-2(1H)-ones are selective HIV IN inhibitors. Preliminary structure-activity relationship (SAR) studies suggested that the divalent metal ion chelators and the nature and position of substituents around the core are important for antiviral potency. Molecular modeling has been used to predict the binding site of the pyrido[2,3-d]pyrimidin-2(1H)-one core in HIV type 1 IN and suggestions are made for improvement of its inhibitory activity.
|
Inhibition of HIV1 recombinant integrase strand transfer activity at 5 ug/ml using biotin-labeled double-stranded HIV-1 LTR U5 donor DNA substrate incubated for 5 mins after substrate addition for 30 mins by ELISA
|
Human immunodeficiency virus 1
|
94.1
%
|
|
Journal : Bioorg Med Chem
Title : 1-Hydroxypyrido[2,3-d]pyrimidin-2(1H)-ones as novel selective HIV integrase inhibitors obtained via privileged substructure-based compound libraries.
Year : 2017
Volume : 25
Issue : 20
First Page : 5779
Last Page : 5789
Authors : Gao P, Zhang L, Sun L, Huang T, Tan J, Zhang J, Zhou Z, Zhao T, Menéndez-Arias L, Pannecouque C, Clercq E, Zhan P, Liu X.
Abstract : A small library containing 3-hydroxyquinazoline-2,4(1H,3H)-dione and 1-hydroxypyrido[2,3-d]pyrimidin-2(1H)-one scaffolds was obtained via the copper(I)-catalyzed azidealkyne cycloaddition (CuAAC) reaction and evaluated for their anti-HIV activity in MT-4 cells. Among the synthesized compounds, several 1-hydroxypyrido[2,3-d]pyrimidin-2(1H)-one derivatives showed remarkable anti-HIV potency with EC50 values ranging from 0.92 to 26.85µM. The most active one, IIA-2, also showed remarkable and selective potency against HIV type 1 integrase (IN). To the best of our knowledge, this is the first report showing that 1-hydroxypyrido[2,3-d]pyrimidin-2(1H)-ones are selective HIV IN inhibitors. Preliminary structure-activity relationship (SAR) studies suggested that the divalent metal ion chelators and the nature and position of substituents around the core are important for antiviral potency. Molecular modeling has been used to predict the binding site of the pyrido[2,3-d]pyrimidin-2(1H)-one core in HIV type 1 IN and suggestions are made for improvement of its inhibitory activity.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
7.47
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
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Inhibition of HIV integrase strand transfer activity
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Human immunodeficiency virus
|
3.8
nM
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and biological evaluation of 3-hydroxyquinazoline-2,4(1H,3H)-diones as dual inhibitors of HIV-1 reverse transcriptase-associated RNase H and integrase.
Year : 2019
Volume : 27
Issue : 17
First Page : 3836
Last Page : 3845
Authors : Gao P, Cheng X, Sun L, Song S, Álvarez M, Luczkowiak J, Pannecouque C, De Clercq E, Menéndez-Arias L, Zhan P, Liu X.
Abstract : A novel series of 3-hydroxyquinazoline-2,4(1H,3H)-diones derivatives has been designed and synthesized. Their biochemical characterization revealed that most of the compounds were effective inhibitors of HIV-1 RNase H activity at sub to low micromolar concentrations. Among them, II-4 was the most potent in enzymatic assays, showing an IC<sub>50</sub> value of 0.41 ± 0.13 μM, almost five times lower than the IC<sub>50</sub> obtained with β-thujaplicinol. In addition, II-4 was also effective in inhibiting HIV-1 IN strand transfer activity (IC<sub>50</sub> = 0.85 ± 0.18 μM) but less potent than raltegravir (IC<sub>50</sub> = 71 ± 14 nM). Despite its relatively low cytotoxicity, the efficiency of II-4 in cell culture was limited by its poor membrane permeability. Nevertheless, structure-activity relationships and molecular modeling studies confirmed the importance of tested 3-hydroxyquinazoline-2,4(1H,3H)-diones as useful leads for further optimization.
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SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
10.31
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
-2.821
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
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Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.46
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.44
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.46
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.44
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
