|
Antiviral activity against HIV1 in MAGI-CCR5 cells
|
Human immunodeficiency virus 1
|
350.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis, in vitro antiviral evaluation, and stability studies of novel alpha-borano-nucleotide analogues of 9-[2-(phosphonomethoxy)ethyl]adenine and (R)-9-[2-(phosphonomethoxy)propyl]adenine.
Year : 2006
Volume : 49
Issue : 26
First Page : 7799
Last Page : 7806
Authors : Barral K, Priet S, Sire J, Neyts J, Balzarini J, Canard B, Alvarez K.
Abstract : We describe here the synthesis of 9-[2-(boranophosphonomethoxy)ethyl]adenine (6a) and (R)-9-[2-(boranophosphonomethoxy)propyl]adenine (6b), the first alpha-boranophosphonate nucleosides in which a borane (BH3) group substitutes one nonbridging oxygen atom of the alpha-phosphonate moiety. H-phosphinates 5a and 5b and alpha-boranophosphonates 6a and 6b were evaluated for their in vitro activity against human immunodeficiency virus (HIV) infected cells and against a panel of DNA or RNA viruses. Compounds 5a, 5b, 6a, and 6b exhibited no significant antiviral activity in vitro and cytotoxicity. To measure the chemical and enzymatic stabilities of the target compounds 6a and 6b, kinetic data of decomposition for derivatives 5a, 5b, 6a, 6b, and standard compounds were studied at 37 degrees C in several media. The alpha-boranophosphonates 6a and 6b were metabolized in culture medium into H-phosphinates 5a and 5b, with half-live values of 5.3 h for 6a and 1.3 h for 6b.
|
Inhibition of HIV1 reverse transcriptase
|
Human immunodeficiency virus 1
|
380.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, anti-HIV activity, and resistance profile of thymidine phosphonomethoxy nucleosides and their bis-isopropyloxymethylcarbonyl (bisPOC) prodrugs.
Year : 2007
Volume : 15
Issue : 16
First Page : 5519
Last Page : 5528
Authors : Mackman RL, Zhang L, Prasad V, Boojamra CG, Douglas J, Grant D, Hui H, Kim CU, Laflamme G, Parrish J, Stoycheva AD, Swaminathan S, Wang K, Cihlar T.
Abstract : Phosphonomethoxy nucleoside analogs of the thymine containing nucleoside reverse transcriptase inhibitors (NRTIs), 3'-azido-2',3'-dideoxythymidine (AZT), 2',3'-didehydro-2',3'-dideoxythymidine (d4T), and 2',3'-dideoxythymidine (ddT), were synthesized. The anti-HIV activity against wild-type and several major nucleoside-resistant strains of HIV-1 was evaluated together with the inhibition of wild-type HIV reverse transcriptase (RT). Phosphonomethoxy analog of d4T, 8 (d4TP), demonstrated antiviral activity with an EC(50) value of 26 microM, whereas, phosphonomethoxy analogs of ddT, 7 (ddTP), and AZT, 6 (AZTP), were both inactive at concentrations up to 200 microM. Bis-isopropyloxymethylcarbonyl (bisPOC) prodrugs improved the anti-HIV activity of 7 and 8 by >150-fold and 29-fold, respectively, allowing for antiviral resistance to be determined. The K65R RT mutant virus was more resistant to the bisPOC prodrugs of 7 and 8 than bisPOC PMPA (tenofovir DF) 1. However, bisPOC prodrug of 7 demonstrated superior resistance toward the RT virus containing multiple thymidine analog mutations (6TAMs) indicating that new phosphonate nucleoside analogs may be suitable for targeting clinically relevant nucleoside resistant HIV-1 strains.
|
Inhibition of wild type HIV reverse transcriptase
|
Human immunodeficiency virus
|
380.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis, anti-HIV activity, and resistance profiles of ribose modified nucleoside phosphonates.
Year : 2007
Volume : 17
Issue : 24
First Page : 6785
Last Page : 6789
Authors : Mackman RL, Boojamra CG, Prasad V, Zhang L, Lin KY, Petrakovsky O, Babusis D, Chen J, Douglas J, Grant D, Hui HC, Kim CU, Markevitch DY, Vela J, Ray A, Cihlar T.
Abstract : A series of nucleoside phosphonate reverse transcriptase (RT) inhibitors have been synthesized and their anti-HIV activity and resistance profiles evaluated. The most potent analog [5-(6-amino-purin-9-yl)-2,5-dihydro-furan-2-yloxymethyl]-phosphonic acid (d4AP) demonstrated a HIV EC(50)=2.1 microM, and the most favorable resistance profile against HIV-1 variants with K65R, M184V or multiple thymidine analog mutations in RT.
|
Inhibition of wild type HIV 3B reverse transcriptase in MT2 cells
|
Human immunodeficiency virus 1
|
380.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and anti-HIV activity of GS-9148 (2'-Fd4AP), a novel nucleoside phosphonate HIV reverse transcriptase inhibitor.
Year : 2008
Volume : 18
Issue : 3
First Page : 1120
Last Page : 1123
Authors : Boojamra CG, Mackman RL, Markevitch DY, Prasad V, Ray AS, Douglas J, Grant D, Kim CU, Cihlar T.
Abstract : GS-9148 (2'-Fd4AP, 4) has been identified as a nucleoside phosphonate reverse transcriptase (RT) inhibitor with activity against wild-type HIV (EC(50)=12 microM). Unlike many clinical RT inhibitors, relevant reverse transcriptase mutants (M184V, K65R, 6-TAMs) maintain a susceptibility to 2'-Fd4AP that is similar to wild-type virus. The 2'-fluorine group was rationally designed into the molecule to improve the selectivity profile and in preliminary studies using HepG2 cells, compound 4 showed no measurable effect on mitochondrial DNA content indicating a low potential for mitochondrial toxicity.
|
Antiviral activity against R5-HIV1Ba-L assessed as inhibition of p24 Gag protein production in human PHA-PBMC by ELISA
|
Human immunodeficiency virus 1
|
32.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Activity against human immunodeficiency virus type 1, intracellular metabolism, and effects on human DNA polymerases of 4'-ethynyl-2-fluoro-2'-deoxyadenosine.
Year : 2007
Volume : 51
Issue : 8
First Page : 2701
Last Page : 2708
Authors : Nakata H, Amano M, Koh Y, Kodama E, Yang G, Bailey CM, Kohgo S, Hayakawa H, Matsuoka M, Anderson KS, Cheng YC, Mitsuya H.
Abstract : We examined the intracytoplasmic anabolism and kinetics of antiviral activity against human immunodeficiency virus type 1 (HIV-1) of a nucleoside reverse transcriptase inhibitor, 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), which has potent activity against wild-type and multidrug-resistant HIV-1 strains. When CEM cells were exposed to 0.1 microM [(3)H]EFdA or [(3)H]3'-azido-2',3'-dideoxythymidine (AZT) for 6 h, the intracellular EFdA-triphosphate (TP) level was 91.6 pmol/10(9) cells, while that of AZT was 396.5 pmol/10(9) cells. When CEM cells were exposed to 10 microM [(3)H]EFdA, the amount of EFdA-TP increased by 22-fold (2,090 pmol/10(9) cells), while the amount of [(3)H]AZT-TP increased only moderately by 2.4-fold (970 pmol/10(9) cells). The intracellular half-life values of EFdA-TP and AZT-TP were approximately 17 and approximately 3 h, respectively. When MT-4 cells were cultured with 0.01 microM EFdA for 24 h, thoroughly washed to remove EFdA, further cultured without EFdA for various periods of time, exposed to HIV-1(NL4-3), and cultured for an additional 5 days, the protection values were 75 and 47%, respectively, after 24 and 48 h with no drug incubation, while those with 1 microM AZT were 55 and 9.2%, respectively. The 50% inhibitory concentration values of EFdA-TP against human polymerases alpha, beta, and gamma were >100 microM, >100 microM, and 10 microM, respectively, while those of ddA-TP were >100 microM, 0.2 microM, and 0.2 microM, respectively. These data warrant further development of EFdA as a potential therapeutic agent for those patients who harbor wild-type HIV-1 and/or multidrug-resistant variants.
|
Antiviral activity against R5-HIV1MDR/MM assessed as inhibition of p24 Gag protein production in human PHA-PBMC by ELISA
|
Human immunodeficiency virus 1
|
82.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Activity against human immunodeficiency virus type 1, intracellular metabolism, and effects on human DNA polymerases of 4'-ethynyl-2-fluoro-2'-deoxyadenosine.
Year : 2007
Volume : 51
Issue : 8
First Page : 2701
Last Page : 2708
Authors : Nakata H, Amano M, Koh Y, Kodama E, Yang G, Bailey CM, Kohgo S, Hayakawa H, Matsuoka M, Anderson KS, Cheng YC, Mitsuya H.
Abstract : We examined the intracytoplasmic anabolism and kinetics of antiviral activity against human immunodeficiency virus type 1 (HIV-1) of a nucleoside reverse transcriptase inhibitor, 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), which has potent activity against wild-type and multidrug-resistant HIV-1 strains. When CEM cells were exposed to 0.1 microM [(3)H]EFdA or [(3)H]3'-azido-2',3'-dideoxythymidine (AZT) for 6 h, the intracellular EFdA-triphosphate (TP) level was 91.6 pmol/10(9) cells, while that of AZT was 396.5 pmol/10(9) cells. When CEM cells were exposed to 10 microM [(3)H]EFdA, the amount of EFdA-TP increased by 22-fold (2,090 pmol/10(9) cells), while the amount of [(3)H]AZT-TP increased only moderately by 2.4-fold (970 pmol/10(9) cells). The intracellular half-life values of EFdA-TP and AZT-TP were approximately 17 and approximately 3 h, respectively. When MT-4 cells were cultured with 0.01 microM EFdA for 24 h, thoroughly washed to remove EFdA, further cultured without EFdA for various periods of time, exposed to HIV-1(NL4-3), and cultured for an additional 5 days, the protection values were 75 and 47%, respectively, after 24 and 48 h with no drug incubation, while those with 1 microM AZT were 55 and 9.2%, respectively. The 50% inhibitory concentration values of EFdA-TP against human polymerases alpha, beta, and gamma were >100 microM, >100 microM, and 10 microM, respectively, while those of ddA-TP were >100 microM, 0.2 microM, and 0.2 microM, respectively. These data warrant further development of EFdA as a potential therapeutic agent for those patients who harbor wild-type HIV-1 and/or multidrug-resistant variants.
|
Antiviral activity against X4-HIV1 NL4-3 assessed as inhibition of p24 Gag protein production in human MT4 cells by MTT assay
|
Human immunodeficiency virus 1
|
0.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Activity against human immunodeficiency virus type 1, intracellular metabolism, and effects on human DNA polymerases of 4'-ethynyl-2-fluoro-2'-deoxyadenosine.
Year : 2007
Volume : 51
Issue : 8
First Page : 2701
Last Page : 2708
Authors : Nakata H, Amano M, Koh Y, Kodama E, Yang G, Bailey CM, Kohgo S, Hayakawa H, Matsuoka M, Anderson KS, Cheng YC, Mitsuya H.
Abstract : We examined the intracytoplasmic anabolism and kinetics of antiviral activity against human immunodeficiency virus type 1 (HIV-1) of a nucleoside reverse transcriptase inhibitor, 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), which has potent activity against wild-type and multidrug-resistant HIV-1 strains. When CEM cells were exposed to 0.1 microM [(3)H]EFdA or [(3)H]3'-azido-2',3'-dideoxythymidine (AZT) for 6 h, the intracellular EFdA-triphosphate (TP) level was 91.6 pmol/10(9) cells, while that of AZT was 396.5 pmol/10(9) cells. When CEM cells were exposed to 10 microM [(3)H]EFdA, the amount of EFdA-TP increased by 22-fold (2,090 pmol/10(9) cells), while the amount of [(3)H]AZT-TP increased only moderately by 2.4-fold (970 pmol/10(9) cells). The intracellular half-life values of EFdA-TP and AZT-TP were approximately 17 and approximately 3 h, respectively. When MT-4 cells were cultured with 0.01 microM EFdA for 24 h, thoroughly washed to remove EFdA, further cultured without EFdA for various periods of time, exposed to HIV-1(NL4-3), and cultured for an additional 5 days, the protection values were 75 and 47%, respectively, after 24 and 48 h with no drug incubation, while those with 1 microM AZT were 55 and 9.2%, respectively. The 50% inhibitory concentration values of EFdA-TP against human polymerases alpha, beta, and gamma were >100 microM, >100 microM, and 10 microM, respectively, while those of ddA-TP were >100 microM, 0.2 microM, and 0.2 microM, respectively. These data warrant further development of EFdA as a potential therapeutic agent for those patients who harbor wild-type HIV-1 and/or multidrug-resistant variants.
|
Antiviral activity against R5-HIV1MDR/C assessed as inhibition of p24 Gag protein production in human PHA-PBMC by ELISA
|
Human immunodeficiency virus 1
|
47.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Activity against human immunodeficiency virus type 1, intracellular metabolism, and effects on human DNA polymerases of 4'-ethynyl-2-fluoro-2'-deoxyadenosine.
Year : 2007
Volume : 51
Issue : 8
First Page : 2701
Last Page : 2708
Authors : Nakata H, Amano M, Koh Y, Kodama E, Yang G, Bailey CM, Kohgo S, Hayakawa H, Matsuoka M, Anderson KS, Cheng YC, Mitsuya H.
Abstract : We examined the intracytoplasmic anabolism and kinetics of antiviral activity against human immunodeficiency virus type 1 (HIV-1) of a nucleoside reverse transcriptase inhibitor, 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), which has potent activity against wild-type and multidrug-resistant HIV-1 strains. When CEM cells were exposed to 0.1 microM [(3)H]EFdA or [(3)H]3'-azido-2',3'-dideoxythymidine (AZT) for 6 h, the intracellular EFdA-triphosphate (TP) level was 91.6 pmol/10(9) cells, while that of AZT was 396.5 pmol/10(9) cells. When CEM cells were exposed to 10 microM [(3)H]EFdA, the amount of EFdA-TP increased by 22-fold (2,090 pmol/10(9) cells), while the amount of [(3)H]AZT-TP increased only moderately by 2.4-fold (970 pmol/10(9) cells). The intracellular half-life values of EFdA-TP and AZT-TP were approximately 17 and approximately 3 h, respectively. When MT-4 cells were cultured with 0.01 microM EFdA for 24 h, thoroughly washed to remove EFdA, further cultured without EFdA for various periods of time, exposed to HIV-1(NL4-3), and cultured for an additional 5 days, the protection values were 75 and 47%, respectively, after 24 and 48 h with no drug incubation, while those with 1 microM AZT were 55 and 9.2%, respectively. The 50% inhibitory concentration values of EFdA-TP against human polymerases alpha, beta, and gamma were >100 microM, >100 microM, and 10 microM, respectively, while those of ddA-TP were >100 microM, 0.2 microM, and 0.2 microM, respectively. These data warrant further development of EFdA as a potential therapeutic agent for those patients who harbor wild-type HIV-1 and/or multidrug-resistant variants.
|
Antiviral activity against R5-HIV1MDR/G assessed as inhibition of p24 Gag protein production in human PHA-PBMC by ELISA
|
Human immunodeficiency virus 1
|
87.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Activity against human immunodeficiency virus type 1, intracellular metabolism, and effects on human DNA polymerases of 4'-ethynyl-2-fluoro-2'-deoxyadenosine.
Year : 2007
Volume : 51
Issue : 8
First Page : 2701
Last Page : 2708
Authors : Nakata H, Amano M, Koh Y, Kodama E, Yang G, Bailey CM, Kohgo S, Hayakawa H, Matsuoka M, Anderson KS, Cheng YC, Mitsuya H.
Abstract : We examined the intracytoplasmic anabolism and kinetics of antiviral activity against human immunodeficiency virus type 1 (HIV-1) of a nucleoside reverse transcriptase inhibitor, 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), which has potent activity against wild-type and multidrug-resistant HIV-1 strains. When CEM cells were exposed to 0.1 microM [(3)H]EFdA or [(3)H]3'-azido-2',3'-dideoxythymidine (AZT) for 6 h, the intracellular EFdA-triphosphate (TP) level was 91.6 pmol/10(9) cells, while that of AZT was 396.5 pmol/10(9) cells. When CEM cells were exposed to 10 microM [(3)H]EFdA, the amount of EFdA-TP increased by 22-fold (2,090 pmol/10(9) cells), while the amount of [(3)H]AZT-TP increased only moderately by 2.4-fold (970 pmol/10(9) cells). The intracellular half-life values of EFdA-TP and AZT-TP were approximately 17 and approximately 3 h, respectively. When MT-4 cells were cultured with 0.01 microM EFdA for 24 h, thoroughly washed to remove EFdA, further cultured without EFdA for various periods of time, exposed to HIV-1(NL4-3), and cultured for an additional 5 days, the protection values were 75 and 47%, respectively, after 24 and 48 h with no drug incubation, while those with 1 microM AZT were 55 and 9.2%, respectively. The 50% inhibitory concentration values of EFdA-TP against human polymerases alpha, beta, and gamma were >100 microM, >100 microM, and 10 microM, respectively, while those of ddA-TP were >100 microM, 0.2 microM, and 0.2 microM, respectively. These data warrant further development of EFdA as a potential therapeutic agent for those patients who harbor wild-type HIV-1 and/or multidrug-resistant variants.
|
Inhibition of murine sarcoma virus-induced transformation of mouse embryo fibroblast C3H/3T3 cells after 6 days
|
Moloney murine leukemia virus
|
230.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Anti-retroviral and cytostatic activity of 2',3'-dideoxyribonucleoside 3'-disulfides.
Year : 2008
Volume : 16
Issue : 14
First Page : 6824
Last Page : 6831
Authors : Gerland B, Désiré J, Balzarini J, Décout JL.
Abstract : Herein, we report the synthesis, antiviral and cytostatic effects of nucleosides bearing a 3'-disulfide function as prodrugs of potentially active 3'-mercaptonucleotides. The lack of the anti-HIV effects in mutant CEM/TK-cells for most of the thymidine disulfides suggests that a phosphorylation step involving thymidine kinase is necessary for the eventual antiviral activity of the thymidine nucleosides. The comparable anti-HIV activities of most of the disulfides and their rapid reduction in CEM cell extracts imply an inhibitory effect of the 2',3'-dideoxy-3'-mercaptothymidine 5'-triphosphate metabolite. The cytostatic effects of the disulfides in CEM/0 and Molt4/C8 cells appeared to be strongly dependent on the nature of the non-nucleosidic disulfide moiety and were decreased in preserving the anti-retroviral activity.
|
Inhibition on HIV1 reverse transcriptase p66/p51
|
Human immunodeficiency virus 1
|
380.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis, and anti-HIV activity of 4'-modified carbocyclic nucleoside phosphonate reverse transcriptase inhibitors.
Year : 2009
Volume : 17
Issue : 4
First Page : 1739
Last Page : 1746
Authors : Boojamra CG, Parrish JP, Sperandio D, Gao Y, Petrakovsky OV, Lee SK, Markevitch DY, Vela JE, Laflamme G, Chen JM, Ray AS, Barron AC, Sparacino ML, Desai MC, Kim CU, Cihlar T, Mackman RL.
Abstract : A diphosphate of a novel cyclopentyl based nucleoside phosphonate with potent inhibition of HIV reverse transcriptase (RT) (20, IC(50)=0.13 microM) has been discovered. In cell culture the parent phosphonate diacid 9 demonstrated antiviral activity EC(50)=16 microM, within two-fold of GS-9148, a prodrug of which is currently under clinical investigation, and within 5-fold of tenofovir (PMPA). In vitro cellular metabolism studies using 9 confirmed that the active diphosphate metabolite is produced albeit at a lower efficiency relative to GS-9148.
|
Antiviral activity against HIV1 LAI in human MT2 cells assessed as inhibition of p24 antigen production by ELISA
|
Human immunodeficiency virus 1
|
650.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Evaluation of hexadecyloxypropyl-9-R-[2-(Phosphonomethoxy)propyl]- adenine, CMX157, as a potential treatment for human immunodeficiency virus type 1 and hepatitis B virus infections.
Year : 2007
Volume : 51
Issue : 10
First Page : 3505
Last Page : 3509
Authors : Painter GR, Almond MR, Trost LC, Lampert BM, Neyts J, De Clercq E, Korba BE, Aldern KA, Beadle JR, Hostetler KY.
Abstract : 9-R-[2-(Phosphonomethoxy)propyl]-adenine (tenofovir) is an acyclic nucleoside phosphonate with antiviral activity against human immunodeficiency virus type 1 (HIV-1) and hepatitis B virus (HBV). Tenofovir is not orally bioavailable but becomes orally active against HIV-1 infection as the disoproxil ester (tenofovir disoproxil fumarate [Viread]). We have developed an alternative strategy for promoting the oral availability of nucleoside phosphonate analogs which involves esterification with a lipid to form a lysolecithin mimic. This mimic can utilize natural lysolecithin uptake pathways in the gut, resulting in high oral availability. Since the mimic is not subject to cleavage in the plasma by nonspecific esterases, it remains intact in the circulation and facilitates uptake by target cells. Significant drops in apparent antiviral 50% effective concentrations (EC(50)s) of up to 3 logs have been observed in comparison with non-lipid-conjugated parent compounds in target cells. We have applied this technology to tenofovir with the goal of increasing oral availability, decreasing the apparent EC(50), and decreasing the potential for nephrotoxicity by reducing the exposure of the kidney to the free dianionic tenofovir. Here we report that, in vitro, the hexadecyloxypropyl ester of tenofovir, CMX157, is 267-fold more active than tenofovir against HIV-1 and 4.5-fold more active against HBV. CMX157 is orally available and has no apparent toxicity when given orally to rats for 7 days at doses of 10, 30, or 100 mg/kg/day. Consequently, CMX157 represents a second-generation tenofovir analog which may have an improved clinical profile.
|
Antiviral activity against HIV1 3B infected in human MT2 cells assessed as inhibition of virus-induced cytopathic effect after 5 days by XTT assay
|
Human immunodeficiency virus 1
|
13.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of GS-9131: Design, synthesis and optimization of amidate prodrugs of the novel nucleoside phosphonate HIV reverse transcriptase (RT) inhibitor GS-9148.
Year : 2010
Volume : 18
Issue : 10
First Page : 3606
Last Page : 3617
Authors : Mackman RL, Ray AS, Hui HC, Zhang L, Birkus G, Boojamra CG, Desai MC, Douglas JL, Gao Y, Grant D, Laflamme G, Lin KY, Markevitch DY, Mishra R, McDermott M, Pakdaman R, Petrakovsky OV, Vela JE, Cihlar T.
Abstract : GS-9148 [(5-(6-amino-purin-9-yl)-4-fluoro-2,5-dihydro-furan-2-yloxymethyl)phosphonic acid] 4 is a novel nucleoside phosphonate HIV-1 reverse transcriptase (RT) inhibitor with a unique resistance profile toward N(t)RTI resistance mutations. To effectively deliver 4 and its active phosphorylated metabolite 15 into target cells, a series of amidate prodrugs were designed as substrates of cathepsin A, an intracellular lysosomal carboxypeptidase highly expressed in peripheral blood mononuclear cells (PBMCs). The ethylalaninyl phosphonamidate prodrug 5 (GS-9131) demonstrated favorable cathepsin A substrate properties, in addition to favorable in vitro intestinal and hepatic stabilities. Following oral dosing (3mg/kg) in Beagle dogs, high levels (>9.0microM) of active metabolite 15 were observed in PBMCs, validating the prodrug design process and leading to the nomination of 5 as a clinical candidate.
|
Antiviral activity against HIV1 NL 4-3 expressing wild type reverse transcriptase infected in human PBMC by ELISA
|
Human immunodeficiency virus 1
|
300.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV.
Year : 2010
Volume : 54
Issue : 7
First Page : 2901
Last Page : 2909
Authors : Lanier ER, Ptak RG, Lampert BM, Keilholz L, Hartman T, Buckheit RW, Mankowski MK, Osterling MC, Almond MR, Painter GR.
Abstract : CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.
|
Selectivity ratio of EC50 for HIV1 7324-1 harboring reverse transcriptase 41L/67N/69N/70R/215F/219E mutant gene infected in human PBMC to EC50 for HIV1 NL 4-3 expressing wild type reverse transcriptase infected in human PBMC
|
Human immunodeficiency virus 1
|
22.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV.
Year : 2010
Volume : 54
Issue : 7
First Page : 2901
Last Page : 2909
Authors : Lanier ER, Ptak RG, Lampert BM, Keilholz L, Hartman T, Buckheit RW, Mankowski MK, Osterling MC, Almond MR, Painter GR.
Abstract : CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.
|
Selectivity ratio of EC50 for HIV1 4755-5 harboring reverse transcriptase 41L/44D/67N/69D/118I/210W/215Y/184V mutant gene infected in human PBMC to EC50 for HIV1 NL 4-3 expressing wild type reverse transcriptase infected in human PBMC
|
Human immunodeficiency virus 1
|
18.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV.
Year : 2010
Volume : 54
Issue : 7
First Page : 2901
Last Page : 2909
Authors : Lanier ER, Ptak RG, Lampert BM, Keilholz L, Hartman T, Buckheit RW, Mankowski MK, Osterling MC, Almond MR, Painter GR.
Abstract : CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.
|
Selectivity ratio of EC50 for HIV1 7303-3 harboring reverse transcriptase 41L/44D/67N/69D/118I/210W/215Y mutant gene infected in human PBMC to EC50 for HIV1 NL 4-3 expressing wild type reverse transcriptase infected in human PBMC
|
Human immunodeficiency virus 1
|
28.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV.
Year : 2010
Volume : 54
Issue : 7
First Page : 2901
Last Page : 2909
Authors : Lanier ER, Ptak RG, Lampert BM, Keilholz L, Hartman T, Buckheit RW, Mankowski MK, Osterling MC, Almond MR, Painter GR.
Abstract : CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.
|
Selectivity ratio of EC50 for HIV1 1617-1 harboring reverse transcriptase 69K/70G/75I/77L/116Y/151M/184V mutant gene infected in human PBMC to EC50 for HIV1 NL 4-3 expressing wild type reverse transcriptase infected in human PBMC
|
Human immunodeficiency virus 1
|
22.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV.
Year : 2010
Volume : 54
Issue : 7
First Page : 2901
Last Page : 2909
Authors : Lanier ER, Ptak RG, Lampert BM, Keilholz L, Hartman T, Buckheit RW, Mankowski MK, Osterling MC, Almond MR, Painter GR.
Abstract : CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.
|
Selectivity ratio of EC50 for HIV1 52534-2 harboring reverse transcriptase 41L//74V/210W/215Y/184V/69SSS mutant gene infected in human PBMC to EC50 for HIV1 NL 4-3 expressing wild type reverse transcriptase infected in human PBMC
|
Human immunodeficiency virus 1
|
22.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV.
Year : 2010
Volume : 54
Issue : 7
First Page : 2901
Last Page : 2909
Authors : Lanier ER, Ptak RG, Lampert BM, Keilholz L, Hartman T, Buckheit RW, Mankowski MK, Osterling MC, Almond MR, Painter GR.
Abstract : CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.
|
Selectivity ratio of EC50 for HIV1 71361-1 harboring reverse transcriptase 65R mutant gene infected in human PBMC to EC50 for HIV1 NL 4-3 expressing wild type reverse transcriptase infected in human PBMC
|
Human immunodeficiency virus 1
|
27.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV.
Year : 2010
Volume : 54
Issue : 7
First Page : 2901
Last Page : 2909
Authors : Lanier ER, Ptak RG, Lampert BM, Keilholz L, Hartman T, Buckheit RW, Mankowski MK, Osterling MC, Almond MR, Painter GR.
Abstract : CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.
|
Selectivity ratio of EC50 for HIV1 8415-2 harboring reverse transcriptase 65R/184V mutant gene infected in human PBMC to EC50 for HIV1 NL 4-3 expressing wild type reverse transcriptase infected in human PBMC
|
Human immunodeficiency virus 1
|
3.3
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV.
Year : 2010
Volume : 54
Issue : 7
First Page : 2901
Last Page : 2909
Authors : Lanier ER, Ptak RG, Lampert BM, Keilholz L, Hartman T, Buckheit RW, Mankowski MK, Osterling MC, Almond MR, Painter GR.
Abstract : CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.
|
Antiviral activity against HIV1 isolate 056 expressing wild type reverse transcriptase gene by phenosense assay
|
Human immunodeficiency virus 1
|
610.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV.
Year : 2010
Volume : 54
Issue : 7
First Page : 2901
Last Page : 2909
Authors : Lanier ER, Ptak RG, Lampert BM, Keilholz L, Hartman T, Buckheit RW, Mankowski MK, Osterling MC, Almond MR, Painter GR.
Abstract : CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.
|
Antiviral activity against HIV1 isolate 057 expressing wild type reverse transcriptase gene by phenosense assay
|
Human immunodeficiency virus 1
|
650.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV.
Year : 2010
Volume : 54
Issue : 7
First Page : 2901
Last Page : 2909
Authors : Lanier ER, Ptak RG, Lampert BM, Keilholz L, Hartman T, Buckheit RW, Mankowski MK, Osterling MC, Almond MR, Painter GR.
Abstract : CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.
|
Antiviral activity against HIV1 isolate 066 harboring reverse transcriptase 184V mutant gene by phenosense assay
|
Human immunodeficiency virus 1
|
530.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV.
Year : 2010
Volume : 54
Issue : 7
First Page : 2901
Last Page : 2909
Authors : Lanier ER, Ptak RG, Lampert BM, Keilholz L, Hartman T, Buckheit RW, Mankowski MK, Osterling MC, Almond MR, Painter GR.
Abstract : CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.
|
Antiviral activity against HIV1 isolate 071 harboring reverse transcriptase 65R/S68N/184V mutant gene by phenosense assay
|
Human immunodeficiency virus 1
|
940.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV.
Year : 2010
Volume : 54
Issue : 7
First Page : 2901
Last Page : 2909
Authors : Lanier ER, Ptak RG, Lampert BM, Keilholz L, Hartman T, Buckheit RW, Mankowski MK, Osterling MC, Almond MR, Painter GR.
Abstract : CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.
|
Antiviral activity against HIV1 isolate 153 harboring reverse transcriptase L74V mutant gene by phenosense assay
|
Human immunodeficiency virus 1
|
480.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV.
Year : 2010
Volume : 54
Issue : 7
First Page : 2901
Last Page : 2909
Authors : Lanier ER, Ptak RG, Lampert BM, Keilholz L, Hartman T, Buckheit RW, Mankowski MK, Osterling MC, Almond MR, Painter GR.
Abstract : CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.
|
Antiviral activity against HIV1 isolate 157 harboring reverse transcriptase L74V/M184V mutant gene by phenosense assay
|
Human immunodeficiency virus 1
|
230.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV.
Year : 2010
Volume : 54
Issue : 7
First Page : 2901
Last Page : 2909
Authors : Lanier ER, Ptak RG, Lampert BM, Keilholz L, Hartman T, Buckheit RW, Mankowski MK, Osterling MC, Almond MR, Painter GR.
Abstract : CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.
|
Antiviral activity against HIV1 isolate 166 harboring reverse transcriptase L74V mutant gene obtained as site-directed mutant of NL4-3 by phenosense assay
|
Human immunodeficiency virus 1
|
540.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV.
Year : 2010
Volume : 54
Issue : 7
First Page : 2901
Last Page : 2909
Authors : Lanier ER, Ptak RG, Lampert BM, Keilholz L, Hartman T, Buckheit RW, Mankowski MK, Osterling MC, Almond MR, Painter GR.
Abstract : CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.
|
Antiviral activity against HIV1 isolate 174 harboring reverse transcriptase M184V mutant gene obtained as site-directed mutant of NL4-3 by phenosense assay
|
Human immunodeficiency virus 1
|
410.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV.
Year : 2010
Volume : 54
Issue : 7
First Page : 2901
Last Page : 2909
Authors : Lanier ER, Ptak RG, Lampert BM, Keilholz L, Hartman T, Buckheit RW, Mankowski MK, Osterling MC, Almond MR, Painter GR.
Abstract : CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.
|
Antiviral activity against HIV1 isolate 188 harboring reverse transcriptase T215Y/M184V mutant gene by phenosense assay
|
Human immunodeficiency virus 1
|
620.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV.
Year : 2010
Volume : 54
Issue : 7
First Page : 2901
Last Page : 2909
Authors : Lanier ER, Ptak RG, Lampert BM, Keilholz L, Hartman T, Buckheit RW, Mankowski MK, Osterling MC, Almond MR, Painter GR.
Abstract : CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.
|
Antiviral activity against HIV1 isolate 203 harboring reverse transcriptase M41L/L210W/T215Y/M184V mutant gene by phenosense assay
|
Human immunodeficiency virus 1
|
750.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV.
Year : 2010
Volume : 54
Issue : 7
First Page : 2901
Last Page : 2909
Authors : Lanier ER, Ptak RG, Lampert BM, Keilholz L, Hartman T, Buckheit RW, Mankowski MK, Osterling MC, Almond MR, Painter GR.
Abstract : CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.
|
Antiviral activity against HIV1 isolate 204 harboring reverse transcriptase M41L/L210W/T215Y/M184V mutant gene by phenosense assay
|
Human immunodeficiency virus 1
|
790.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV.
Year : 2010
Volume : 54
Issue : 7
First Page : 2901
Last Page : 2909
Authors : Lanier ER, Ptak RG, Lampert BM, Keilholz L, Hartman T, Buckheit RW, Mankowski MK, Osterling MC, Almond MR, Painter GR.
Abstract : CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.
|
Antiviral activity against HIV1 isolate 211 harboring reverse transcriptase D67N/K70R/T215F/K219E/M184V mutant gene by phenosense assay
|
Human immunodeficiency virus 1
|
700.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV.
Year : 2010
Volume : 54
Issue : 7
First Page : 2901
Last Page : 2909
Authors : Lanier ER, Ptak RG, Lampert BM, Keilholz L, Hartman T, Buckheit RW, Mankowski MK, Osterling MC, Almond MR, Painter GR.
Abstract : CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.
|
Antiviral activity against HIV1 isolate 215 harboring reverse transcriptase D67N/K70E mutant gene by phenosense assay
|
Human immunodeficiency virus 1
|
740.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV.
Year : 2010
Volume : 54
Issue : 7
First Page : 2901
Last Page : 2909
Authors : Lanier ER, Ptak RG, Lampert BM, Keilholz L, Hartman T, Buckheit RW, Mankowski MK, Osterling MC, Almond MR, Painter GR.
Abstract : CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.
|
Antiviral activity against HIV1 isolate 217 harboring reverse transcriptase D67N/K70E/M184V mutant gene by phenosense assay
|
Human immunodeficiency virus 1
|
500.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV.
Year : 2010
Volume : 54
Issue : 7
First Page : 2901
Last Page : 2909
Authors : Lanier ER, Ptak RG, Lampert BM, Keilholz L, Hartman T, Buckheit RW, Mankowski MK, Osterling MC, Almond MR, Painter GR.
Abstract : CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.
|
Antiviral activity against HIV1 isolate 220 harboring reverse transcriptase K70E/M184V mutant gene by phenosense assay
|
Human immunodeficiency virus 1
|
470.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV.
Year : 2010
Volume : 54
Issue : 7
First Page : 2901
Last Page : 2909
Authors : Lanier ER, Ptak RG, Lampert BM, Keilholz L, Hartman T, Buckheit RW, Mankowski MK, Osterling MC, Almond MR, Painter GR.
Abstract : CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.
|
Antiviral activity against HBV infected in human HepG 2.215 cells assessed as inhibition of DNA replication by RT-PCR analysis
|
Hepatitis B virus
|
540.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and biological assay of 4-aryl-6-chloro-quinoline derivatives as novel non-nucleoside anti-HBV agents.
Year : 2011
Volume : 19
Issue : 4
First Page : 1400
Last Page : 1408
Authors : Guo RH, Zhang Q, Ma YB, Huang XY, Luo J, Wang LJ, Geng CA, Zhang XM, Zhou J, Jiang ZY, Chen JJ.
Abstract : A series of 4-aryl-6-chloro-quinoline derivatives were synthesized and evaluated for their anti-hepatitis B virus (HBV) activities, namely the abilities to inhibit the secretion of HBV surface antigen (HBsAg), HBV e antigen (HBeAg), and replication of HBV DNA in HepG 2.2.15 cells. Most of the compounds exhibited moderate inhibitory activity against the secretion of HBsAg and HBeAg. Nine compounds (3, 5, 6, 7, 10, 14, 17, 20, 24) showed significant inhibition against HBV DNA replication with IC(50) values in the range of 4.4-9.8 μM, which were comparative to that of positive control tenofovir. Of them, compounds 10, 17, and 20 had low cytotoxicities, resulting in high SI values, >551.2, >143.7, and >284.5, respectively.
|
Antiviral activity against R5 tropic HIV1 YU.2 infected in human PBMC assessed as inhibition of p24 antigen production after 2 hrs by ELISA
|
Human immunodeficiency virus 1
|
884.24
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Reverse transcriptase inhibitors as potential colorectal microbicides.
Year : 2009
Volume : 53
Issue : 5
First Page : 1797
Last Page : 1807
Authors : Herrera C, Cranage M, McGowan I, Anton P, Shattock RJ.
Abstract : We investigated whether reverse transcriptase (RT) inhibitors (RTI) can be combined to inhibit human immunodeficiency virus type 1 (HIV-1) infection of colorectal tissue ex vivo as part of a strategy to develop an effective rectal microbicide. The nucleotide RTI (NRTI) PMPA (tenofovir) and two nonnucleoside RTI (NNRTI), UC-781 and TMC120 (dapivirine), were evaluated. Each compound inhibited the replication of the HIV isolates tested in TZM-bl cells, peripheral blood mononuclear cells, and colorectal explants. Dual combinations of the three compounds, either NRTI-NNRTI or NNRTI-NNRTI combinations, were more active than any of the individual compounds in both cellular and tissue models. Combinations were key to inhibiting infection by NRTI- and NNRTI-resistant isolates in all models tested. Moreover, we found that the replication capacities of HIV-1 isolates in colorectal explants were affected by single point mutations in RT that confer resistance to RTI. These data demonstrate that colorectal explants can be used to screen compounds for potential efficacy as part of a combination microbicide and to determine the mucosal fitness of RTI-resistant isolates. These findings may have important implications for the rational design of effective rectal microbicides.
|
Antiviral activity against HIV1 isolate 8415-2 harboring reverse transcriptase K65R mutant co-expressing M184V mutant infected in human TZM-b1 cells after 2 hrs by luciferase assays
|
Human immunodeficiency virus 1
|
820.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Reverse transcriptase inhibitors as potential colorectal microbicides.
Year : 2009
Volume : 53
Issue : 5
First Page : 1797
Last Page : 1807
Authors : Herrera C, Cranage M, McGowan I, Anton P, Shattock RJ.
Abstract : We investigated whether reverse transcriptase (RT) inhibitors (RTI) can be combined to inhibit human immunodeficiency virus type 1 (HIV-1) infection of colorectal tissue ex vivo as part of a strategy to develop an effective rectal microbicide. The nucleotide RTI (NRTI) PMPA (tenofovir) and two nonnucleoside RTI (NNRTI), UC-781 and TMC120 (dapivirine), were evaluated. Each compound inhibited the replication of the HIV isolates tested in TZM-bl cells, peripheral blood mononuclear cells, and colorectal explants. Dual combinations of the three compounds, either NRTI-NNRTI or NNRTI-NNRTI combinations, were more active than any of the individual compounds in both cellular and tissue models. Combinations were key to inhibiting infection by NRTI- and NNRTI-resistant isolates in all models tested. Moreover, we found that the replication capacities of HIV-1 isolates in colorectal explants were affected by single point mutations in RT that confer resistance to RTI. These data demonstrate that colorectal explants can be used to screen compounds for potential efficacy as part of a combination microbicide and to determine the mucosal fitness of RTI-resistant isolates. These findings may have important implications for the rational design of effective rectal microbicides.
|
Antiviral activity against 125 TCID50 wild type HIV1 LAI infected in human H9 cells assessed as reduction in viral replication measured on day 7 post infection by reverse transcriptase activity
|
Human immunodeficiency virus 1
|
230.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Acyclic nucleoside thiophosphonates as potent inhibitors of HIV and HBV replication.
Year : 2011
Volume : 46
Issue : 9
First Page : 4281
Last Page : 4288
Authors : Barral K, Weck C, Payrot N, Roux L, Durafour C, Zoulim F, Neyts J, Balzarini J, Canard B, Priet S, Alvarez K.
Abstract : 9-[2-(Thiophosphonomethoxy)ethyl]adenine 3 and (R)-9-[2-(Thiophosphonomethoxy)propyl]adenine 4 were synthesized as the first thiophosphonate nucleosides bearing a sulfur atom at the α-position of the acyclic nucleoside phosphonates PMEA and PMPA. Thiophosphonates S-PMEA 3 and S-PMPA 4 were evaluated for in vitro activity against HIV-1 (subtypes A to G), HIV-2 and HBV-infected cells, and found to exhibit potent antiretroviral activity. We showed that their diphosphate forms S-PMEApp 5 and S-PMPApp 6 are readily incorporated by wild-type (WT) HIV-1 RT into DNA and act as DNA chain terminators. Compounds 3 and 4 were evaluated for in vitro activity against a broad panel of DNA and RNA viruses and displayed beside HIV a moderate activity against herpes simplex virus and vaccinia viruses. In order to measure enzymatic stabilities of the target derivatives 3 and 4, kinetic data and decomposition pathways were studied at 37 °C in several media.
|
Antiviral activity against HIV1 clade B isolate 2101 infected in human H9 cells assessed as inhibition of viral replication
|
Human immunodeficiency virus 1
|
240.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Acyclic nucleoside thiophosphonates as potent inhibitors of HIV and HBV replication.
Year : 2011
Volume : 46
Issue : 9
First Page : 4281
Last Page : 4288
Authors : Barral K, Weck C, Payrot N, Roux L, Durafour C, Zoulim F, Neyts J, Balzarini J, Canard B, Priet S, Alvarez K.
Abstract : 9-[2-(Thiophosphonomethoxy)ethyl]adenine 3 and (R)-9-[2-(Thiophosphonomethoxy)propyl]adenine 4 were synthesized as the first thiophosphonate nucleosides bearing a sulfur atom at the α-position of the acyclic nucleoside phosphonates PMEA and PMPA. Thiophosphonates S-PMEA 3 and S-PMPA 4 were evaluated for in vitro activity against HIV-1 (subtypes A to G), HIV-2 and HBV-infected cells, and found to exhibit potent antiretroviral activity. We showed that their diphosphate forms S-PMEApp 5 and S-PMPApp 6 are readily incorporated by wild-type (WT) HIV-1 RT into DNA and act as DNA chain terminators. Compounds 3 and 4 were evaluated for in vitro activity against a broad panel of DNA and RNA viruses and displayed beside HIV a moderate activity against herpes simplex virus and vaccinia viruses. In order to measure enzymatic stabilities of the target derivatives 3 and 4, kinetic data and decomposition pathways were studied at 37 °C in several media.
|
Antiviral activity against HIV1 clade B isolate 1722 infected in human H9 cells assessed as inhibition of viral replication
|
Human immunodeficiency virus 1
|
690.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Acyclic nucleoside thiophosphonates as potent inhibitors of HIV and HBV replication.
Year : 2011
Volume : 46
Issue : 9
First Page : 4281
Last Page : 4288
Authors : Barral K, Weck C, Payrot N, Roux L, Durafour C, Zoulim F, Neyts J, Balzarini J, Canard B, Priet S, Alvarez K.
Abstract : 9-[2-(Thiophosphonomethoxy)ethyl]adenine 3 and (R)-9-[2-(Thiophosphonomethoxy)propyl]adenine 4 were synthesized as the first thiophosphonate nucleosides bearing a sulfur atom at the α-position of the acyclic nucleoside phosphonates PMEA and PMPA. Thiophosphonates S-PMEA 3 and S-PMPA 4 were evaluated for in vitro activity against HIV-1 (subtypes A to G), HIV-2 and HBV-infected cells, and found to exhibit potent antiretroviral activity. We showed that their diphosphate forms S-PMEApp 5 and S-PMPApp 6 are readily incorporated by wild-type (WT) HIV-1 RT into DNA and act as DNA chain terminators. Compounds 3 and 4 were evaluated for in vitro activity against a broad panel of DNA and RNA viruses and displayed beside HIV a moderate activity against herpes simplex virus and vaccinia viruses. In order to measure enzymatic stabilities of the target derivatives 3 and 4, kinetic data and decomposition pathways were studied at 37 °C in several media.
|
Antiviral activity against HIV1 clade C isolate 2914 infected in human H9 cells assessed as inhibition of viral replication
|
Human immunodeficiency virus 1
|
340.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Acyclic nucleoside thiophosphonates as potent inhibitors of HIV and HBV replication.
Year : 2011
Volume : 46
Issue : 9
First Page : 4281
Last Page : 4288
Authors : Barral K, Weck C, Payrot N, Roux L, Durafour C, Zoulim F, Neyts J, Balzarini J, Canard B, Priet S, Alvarez K.
Abstract : 9-[2-(Thiophosphonomethoxy)ethyl]adenine 3 and (R)-9-[2-(Thiophosphonomethoxy)propyl]adenine 4 were synthesized as the first thiophosphonate nucleosides bearing a sulfur atom at the α-position of the acyclic nucleoside phosphonates PMEA and PMPA. Thiophosphonates S-PMEA 3 and S-PMPA 4 were evaluated for in vitro activity against HIV-1 (subtypes A to G), HIV-2 and HBV-infected cells, and found to exhibit potent antiretroviral activity. We showed that their diphosphate forms S-PMEApp 5 and S-PMPApp 6 are readily incorporated by wild-type (WT) HIV-1 RT into DNA and act as DNA chain terminators. Compounds 3 and 4 were evaluated for in vitro activity against a broad panel of DNA and RNA viruses and displayed beside HIV a moderate activity against herpes simplex virus and vaccinia viruses. In order to measure enzymatic stabilities of the target derivatives 3 and 4, kinetic data and decomposition pathways were studied at 37 °C in several media.
|
Antiviral activity against HIV1 clade C isolate 4110 infected in human H9 cells assessed as inhibition of viral replication
|
Human immunodeficiency virus 1
|
830.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Acyclic nucleoside thiophosphonates as potent inhibitors of HIV and HBV replication.
Year : 2011
Volume : 46
Issue : 9
First Page : 4281
Last Page : 4288
Authors : Barral K, Weck C, Payrot N, Roux L, Durafour C, Zoulim F, Neyts J, Balzarini J, Canard B, Priet S, Alvarez K.
Abstract : 9-[2-(Thiophosphonomethoxy)ethyl]adenine 3 and (R)-9-[2-(Thiophosphonomethoxy)propyl]adenine 4 were synthesized as the first thiophosphonate nucleosides bearing a sulfur atom at the α-position of the acyclic nucleoside phosphonates PMEA and PMPA. Thiophosphonates S-PMEA 3 and S-PMPA 4 were evaluated for in vitro activity against HIV-1 (subtypes A to G), HIV-2 and HBV-infected cells, and found to exhibit potent antiretroviral activity. We showed that their diphosphate forms S-PMEApp 5 and S-PMPApp 6 are readily incorporated by wild-type (WT) HIV-1 RT into DNA and act as DNA chain terminators. Compounds 3 and 4 were evaluated for in vitro activity against a broad panel of DNA and RNA viruses and displayed beside HIV a moderate activity against herpes simplex virus and vaccinia viruses. In order to measure enzymatic stabilities of the target derivatives 3 and 4, kinetic data and decomposition pathways were studied at 37 °C in several media.
|
Antiviral activity against HIV1 clade D isolate 1649 infected in human H9 cells assessed as inhibition of viral replication
|
Human immunodeficiency virus 1
|
100.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Acyclic nucleoside thiophosphonates as potent inhibitors of HIV and HBV replication.
Year : 2011
Volume : 46
Issue : 9
First Page : 4281
Last Page : 4288
Authors : Barral K, Weck C, Payrot N, Roux L, Durafour C, Zoulim F, Neyts J, Balzarini J, Canard B, Priet S, Alvarez K.
Abstract : 9-[2-(Thiophosphonomethoxy)ethyl]adenine 3 and (R)-9-[2-(Thiophosphonomethoxy)propyl]adenine 4 were synthesized as the first thiophosphonate nucleosides bearing a sulfur atom at the α-position of the acyclic nucleoside phosphonates PMEA and PMPA. Thiophosphonates S-PMEA 3 and S-PMPA 4 were evaluated for in vitro activity against HIV-1 (subtypes A to G), HIV-2 and HBV-infected cells, and found to exhibit potent antiretroviral activity. We showed that their diphosphate forms S-PMEApp 5 and S-PMPApp 6 are readily incorporated by wild-type (WT) HIV-1 RT into DNA and act as DNA chain terminators. Compounds 3 and 4 were evaluated for in vitro activity against a broad panel of DNA and RNA viruses and displayed beside HIV a moderate activity against herpes simplex virus and vaccinia viruses. In order to measure enzymatic stabilities of the target derivatives 3 and 4, kinetic data and decomposition pathways were studied at 37 °C in several media.
|
Antiviral activity against HIV1 clade A/E isolate 2165 infected in human H9 cells assessed as inhibition of viral replication
|
Human immunodeficiency virus 1
|
510.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Acyclic nucleoside thiophosphonates as potent inhibitors of HIV and HBV replication.
Year : 2011
Volume : 46
Issue : 9
First Page : 4281
Last Page : 4288
Authors : Barral K, Weck C, Payrot N, Roux L, Durafour C, Zoulim F, Neyts J, Balzarini J, Canard B, Priet S, Alvarez K.
Abstract : 9-[2-(Thiophosphonomethoxy)ethyl]adenine 3 and (R)-9-[2-(Thiophosphonomethoxy)propyl]adenine 4 were synthesized as the first thiophosphonate nucleosides bearing a sulfur atom at the α-position of the acyclic nucleoside phosphonates PMEA and PMPA. Thiophosphonates S-PMEA 3 and S-PMPA 4 were evaluated for in vitro activity against HIV-1 (subtypes A to G), HIV-2 and HBV-infected cells, and found to exhibit potent antiretroviral activity. We showed that their diphosphate forms S-PMEApp 5 and S-PMPApp 6 are readily incorporated by wild-type (WT) HIV-1 RT into DNA and act as DNA chain terminators. Compounds 3 and 4 were evaluated for in vitro activity against a broad panel of DNA and RNA viruses and displayed beside HIV a moderate activity against herpes simplex virus and vaccinia viruses. In order to measure enzymatic stabilities of the target derivatives 3 and 4, kinetic data and decomposition pathways were studied at 37 °C in several media.
|
Antiviral activity against HIV1 clade F isolate 2338 infected in human H9 cells assessed as inhibition of viral replication
|
Human immunodeficiency virus 1
|
40.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Acyclic nucleoside thiophosphonates as potent inhibitors of HIV and HBV replication.
Year : 2011
Volume : 46
Issue : 9
First Page : 4281
Last Page : 4288
Authors : Barral K, Weck C, Payrot N, Roux L, Durafour C, Zoulim F, Neyts J, Balzarini J, Canard B, Priet S, Alvarez K.
Abstract : 9-[2-(Thiophosphonomethoxy)ethyl]adenine 3 and (R)-9-[2-(Thiophosphonomethoxy)propyl]adenine 4 were synthesized as the first thiophosphonate nucleosides bearing a sulfur atom at the α-position of the acyclic nucleoside phosphonates PMEA and PMPA. Thiophosphonates S-PMEA 3 and S-PMPA 4 were evaluated for in vitro activity against HIV-1 (subtypes A to G), HIV-2 and HBV-infected cells, and found to exhibit potent antiretroviral activity. We showed that their diphosphate forms S-PMEApp 5 and S-PMPApp 6 are readily incorporated by wild-type (WT) HIV-1 RT into DNA and act as DNA chain terminators. Compounds 3 and 4 were evaluated for in vitro activity against a broad panel of DNA and RNA viruses and displayed beside HIV a moderate activity against herpes simplex virus and vaccinia viruses. In order to measure enzymatic stabilities of the target derivatives 3 and 4, kinetic data and decomposition pathways were studied at 37 °C in several media.
|
Antiviral activity against HIV1 clade G isolate 3187 infected in human H9 cells assessed as inhibition of viral replication
|
Human immunodeficiency virus 1
|
150.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Acyclic nucleoside thiophosphonates as potent inhibitors of HIV and HBV replication.
Year : 2011
Volume : 46
Issue : 9
First Page : 4281
Last Page : 4288
Authors : Barral K, Weck C, Payrot N, Roux L, Durafour C, Zoulim F, Neyts J, Balzarini J, Canard B, Priet S, Alvarez K.
Abstract : 9-[2-(Thiophosphonomethoxy)ethyl]adenine 3 and (R)-9-[2-(Thiophosphonomethoxy)propyl]adenine 4 were synthesized as the first thiophosphonate nucleosides bearing a sulfur atom at the α-position of the acyclic nucleoside phosphonates PMEA and PMPA. Thiophosphonates S-PMEA 3 and S-PMPA 4 were evaluated for in vitro activity against HIV-1 (subtypes A to G), HIV-2 and HBV-infected cells, and found to exhibit potent antiretroviral activity. We showed that their diphosphate forms S-PMEApp 5 and S-PMPApp 6 are readily incorporated by wild-type (WT) HIV-1 RT into DNA and act as DNA chain terminators. Compounds 3 and 4 were evaluated for in vitro activity against a broad panel of DNA and RNA viruses and displayed beside HIV a moderate activity against herpes simplex virus and vaccinia viruses. In order to measure enzymatic stabilities of the target derivatives 3 and 4, kinetic data and decomposition pathways were studied at 37 °C in several media.
|
Antiviral activity against Hepatitis B virus infected in human HepG2(2.2.15) cells assessed as reduction in viral DNA replication
|
Hepatitis B virus
|
890.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis, biological evaluation and structure-activity relationships of glycyrrhetinic acid derivatives as novel anti-hepatitis B virus agents.
Year : 2012
Volume : 22
Issue : 10
First Page : 3473
Last Page : 3479
Authors : Wang LJ, Geng CA, Ma YB, Huang XY, Luo J, Chen H, Zhang XM, Chen JJ.
Abstract : Fifty-seven derivatives of glycyrrhetinic acid (GA) were synthesized, and their anti-hepatitis B virus (HBV) activity was evaluated in HepG 2.2.15 cells. Among them, sixteen compounds showed greater anti-HBV activity than GA, especially, compounds 29, 32, 35, 41 exhibited significantly inhibitory activities against HBV DNA replication with IC(50) values of 5.71, 5.36, 8.90 and 9.08 μM, respectively. The structure-activity relationships (SARs) of GA derivatives were discussed for exploring novel anti-HBV agents.
|
Antiviral activity against Hepatitis B virus infected in human HepG2(2.2.15) cells assessed as inhibition of viral DNA replication by RT-PCR analysis
|
Hepatitis B virus
|
770.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, structure-activity relationships and biological evaluation of caudatin derivatives as novel anti-hepatitis B virus agents.
Year : 2012
Volume : 20
Issue : 9
First Page : 2877
Last Page : 2888
Authors : Wang LJ, Geng CA, Ma YB, Huang XY, Luo J, Chen H, Guo RH, Zhang XM, Chen JJ.
Abstract : A series of caudatin derivatives were synthesized, and their anti-hepatitis B virus (HBV) activity was evaluated in HepG 2.2.15 cells. Most of the 3-O-substituted caudatin derivatives showed effective anti-HBV activity. Among the tested compounds, six compounds (2e-2h, 2l, 2r) exhibited significantly inhibitory activity against HBV DNA replication with IC(50) values in the range of 2.82-7.48 μM. Interestingly, two compounds (2e, 2f) had potent activity inhibiting not only the secretion of HBsAg (IC(50)=18.68 μM, 21.71 μM), HBeAg (IC(50)=13.16 μM, 33.73 μM), but also HBV DNA replication (IC(50)=7.48 μM, 3.63 μM). The structure-activity relationships (SARs) of caudatin derivatives had been discussed, which were useful for caudatin derivatives to be explored and developed as novel anti-HBV agents.
|
Antiviral activity against Hepatitis B virus infected in human HepG2(2.2.15) cells assessed as inhibition of viral DNA replication by PCR analysis
|
Hepatitis B virus
|
680.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design, synthesis, and molecular hybrids of caudatin and cinnamic acids as novel anti-hepatitis B virus agents.
Year : 2012
Volume : 54
First Page : 352
Last Page : 365
Authors : Wang LJ, Geng CA, Ma YB, Luo J, Huang XY, Chen H, Zhou NJ, Zhang XM, Chen JJ.
Abstract : Forty-six conjugated derivatives of caudatin with substituted cinnamic acids were synthesized, and their anti-hepatitis B virus (HBV) activity was evaluated in HepG 2.2.15 cells. Most of the derivatives exhibited potent anti-HBV activity, especially inhibiting the HBV DNA replication with the IC(50) values from 2.44 to 22.89 μΜ. Compound 18 showed significant activity against the secretion of HBsAg, HBeAg, and HBV DNA replication with IC(50) values of 5.52, 5.52, 2.44 μΜ, respectively, and had good safety (LD(50) > 1250 mg/kg) according to the acute toxicity study. Preliminary mechanism investigation suggested that compound 18 exerted antivirus effects via interfering HBV X promoter and enhancer I to influence HBV transcriptions.
|
Inhibition of human liver OATP1B1 expressed in HEK293 Flp-In cells assessed as reduction in E17-betaG uptake at 20 uM by scintillation counting
|
Homo sapiens
|
18.4
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP1B3 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E17-betaG uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
33.6
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP2B1 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E3S uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
23.3
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Antiviral activity against HBV infected in human HepG2.2.15 cells assessed as inhibition of viral DNA replication
|
Hepatitis B virus
|
490.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of hemslecin A derivatives: a new class of hepatitis B virus inhibitors.
Year : 2013
Volume : 23
Issue : 5
First Page : 1201
Last Page : 1205
Authors : Guo RH, Geng CA, Huang XY, Ma YB, Zhang Q, Wang LJ, Zhang XM, Zhang RP, Chen JJ.
Abstract : A series of hemslecin A derivatives were synthesized and evaluated for their anti-hepatitis B virus (HBV) activities, namely, inhibiting the secretion of hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), and HBV DNA replication on HepG 2.2.15 cells. Most of the derivatives showed enhanced anti-HBV activities, of which compounds A1-A7, B5, C and E exhibited significant activities inhibiting HBV DNA replication with IC(50) values of 2.8-11.6 μM, comparable to that of the positive control, tenofovir. Compounds A1-A3, A5, B5, and C displayed low cytotoxicities, which resulted in high SI values of 89.7, 55.6, 77.8, >83.4, >55.8, and >150.5, respectively.
|
Antiviral activity against HBV infected in human HepG2.2.15 cells assessed as inhibition of DNA replication
|
Hepatitis B virus
|
710.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis, structure-activity relationships and biological evaluation of dehydroandrographolide and andrographolide derivatives as novel anti-hepatitis B virus agents.
Year : 2014
Volume : 24
Issue : 10
First Page : 2353
Last Page : 2359
Authors : Chen H, Ma YB, Huang XY, Geng CA, Zhao Y, Wang LJ, Guo RH, Liang WJ, Zhang XM, Chen JJ.
Abstract : Dehydroandrographolide and andrographolide, two natural diterpenoids isolated from Andrographis paniculata possessed activity against HBV DNA replication with IC50 values of 22.58 and 54.07μM and low SI values of 8.7 and 3.7 in our random assay. Consequently, 48 derivatives of dehydroandrographolide and andrographolide were synthesized and evaluated for their anti-HBV properties to yield a series of active derivatives with lower cytotoxicity, including 14 derivatives against HBsAg secretion, 19 derivatives against HBeAg secretion and 38 derivatives against HBV DNA replication. Interestingly, compound 4e could inhibit not only HBsAg and HBeAg secretions but also HBV DNA replication with SI values of 20.3, 125.0 and 104.9. Furthermore, the most active compound 2c with SI value higher than 165.1 inhibiting HBV DNA replication was revealed with the optimal logP value of 1.78 and logD values. Structure-activity relationships (SARs) of the derivatives were disclosed for guiding the future research toward the discovery of new anti-HBV drugs.
|
Inhibition of HBV DNA replication in HepG2(2.2.15) cells exposed to fresh medium supplemented with compound every other day for additional 5 days by real-time PCR-fluorescent probing method
|
Hepatitis B virus
|
500.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of erythrocentaurin derivatives as a new class of hepatitis B virus inhibitors.
Year : 2015
Volume : 25
Issue : 7
First Page : 1568
Last Page : 1571
Authors : Geng CA, Huang XY, Ma YB, Zhang XM, Chen JJ.
Abstract : Twenty-four derivatives of erythrocentaurin (ET) were synthesized and evaluated for their anti-HBV activities on HepG 2.2.15 cell line in vitro. Eight compounds 1, 2, 5, 8, 9, 1e, 1k, and 1m increased activity against HBV DNA replication with the SI values higher than 11. In particular, derivatives 1e and 1k exhibited the most potent inhibition on HBV DNA replication with the IC50 values of 0.026 mM (SI>70.8) and 0.045 mM (SI>36.0), respectively. The primary structure-activity relationships (SARs) of ET derivatives were summarized for exploring potent anti-HBV agents.
|
Antiviral activity against CXCR4-tropic HIV-1 NL4-3 infected in human PHA-stimulated PBMC assessed as inhibition of viral replication by measuring reduction in p24 antigen production preincubated with cells for 30 mins followed by viral infection measured on day 10 post infection in presence of IL-2 by ELISA
|
Human immunodeficiency virus 1
|
380.0
nM
|
|
Journal : J Med Chem
Title : Expanding the Antiviral Spectrum of 3-Fluoro-2-(phosphonomethoxy)propyl Acyclic Nucleoside Phosphonates: Diamyl Aspartate Amidate Prodrugs.
Year : 2017
Volume : 60
Issue : 14
First Page : 6220
Last Page : 6238
Authors : Luo M, Groaz E, Andrei G, Snoeck R, Kalkeri R, Ptak RG, Hartman T, Buckheit RW, Schols D, De Jonghe S, Herdewijn P.
Abstract : Acyclic nucleosides containing a 3-fluoro-2-(phosphonomethoxy)propyl (FPMP) side chain are known to be moderately potent antihuman immunodeficiency virus (HIV) agents, while being completely devoid of antiviral activity against a wide range of DNA viruses. The derivatization of the phosphonic acid functionality of FPMPs with a diamyl aspartate phenoxyamidate group led to a novel generation of compounds that not only demonstrate drastically improved antiretroviral potency but also are characterized by an expanded spectrum of activity that also covers hepatitis B and herpes viruses. The best compound, the (S)-FPMPA amidate prodrug, exerts anti-HIV-1 activity in TZM-bl and peripheral blood mononuclear cells at low nanomolar concentrations and displays excellent potency against hepatitis B virus (HBV) and varicella-zoster virus (VZV). This prodrug is stable in acid and human plasma media, but it is efficiently processed in human liver microsomes with a half-life of 2 min. The (R) isomeric guanine derivative emerged as a selectively active anti-HIV and anti-HBV inhibitor, while being nontoxic to human hepatoblastoma cells. Notably, the pyrimidine containing prodrug (S)-Asp-FPMPC is the only congener within this series to demonstrate micromolar antihuman cytomegalovirus (HCMV) potency.
|
Antiviral activity against tenofovir-resistant CXCR4-tropic HIV-1 NL4-3 harboring reverse transcriptase K65R mutant infected in human MT4 cells assessed as inhibition of viral replication inhibition of virus-induced cytopathic effect after 6 days by XTT dye based assay
|
Human immunodeficiency virus 1
|
100.0
nM
|
|
Journal : J Med Chem
Title : Expanding the Antiviral Spectrum of 3-Fluoro-2-(phosphonomethoxy)propyl Acyclic Nucleoside Phosphonates: Diamyl Aspartate Amidate Prodrugs.
Year : 2017
Volume : 60
Issue : 14
First Page : 6220
Last Page : 6238
Authors : Luo M, Groaz E, Andrei G, Snoeck R, Kalkeri R, Ptak RG, Hartman T, Buckheit RW, Schols D, De Jonghe S, Herdewijn P.
Abstract : Acyclic nucleosides containing a 3-fluoro-2-(phosphonomethoxy)propyl (FPMP) side chain are known to be moderately potent antihuman immunodeficiency virus (HIV) agents, while being completely devoid of antiviral activity against a wide range of DNA viruses. The derivatization of the phosphonic acid functionality of FPMPs with a diamyl aspartate phenoxyamidate group led to a novel generation of compounds that not only demonstrate drastically improved antiretroviral potency but also are characterized by an expanded spectrum of activity that also covers hepatitis B and herpes viruses. The best compound, the (S)-FPMPA amidate prodrug, exerts anti-HIV-1 activity in TZM-bl and peripheral blood mononuclear cells at low nanomolar concentrations and displays excellent potency against hepatitis B virus (HBV) and varicella-zoster virus (VZV). This prodrug is stable in acid and human plasma media, but it is efficiently processed in human liver microsomes with a half-life of 2 min. The (R) isomeric guanine derivative emerged as a selectively active anti-HIV and anti-HBV inhibitor, while being nontoxic to human hepatoblastoma cells. Notably, the pyrimidine containing prodrug (S)-Asp-FPMPC is the only congener within this series to demonstrate micromolar antihuman cytomegalovirus (HCMV) potency.
|
Antiviral activity against CXCR4-tropic HIV-1 NL4-3 infected in human MT4 cells assessed as inhibition of virus-induced cytopathic effect after 6 days by XTT dye based assay
|
Human immunodeficiency virus 1
|
60.0
nM
|
|
Journal : J Med Chem
Title : Expanding the Antiviral Spectrum of 3-Fluoro-2-(phosphonomethoxy)propyl Acyclic Nucleoside Phosphonates: Diamyl Aspartate Amidate Prodrugs.
Year : 2017
Volume : 60
Issue : 14
First Page : 6220
Last Page : 6238
Authors : Luo M, Groaz E, Andrei G, Snoeck R, Kalkeri R, Ptak RG, Hartman T, Buckheit RW, Schols D, De Jonghe S, Herdewijn P.
Abstract : Acyclic nucleosides containing a 3-fluoro-2-(phosphonomethoxy)propyl (FPMP) side chain are known to be moderately potent antihuman immunodeficiency virus (HIV) agents, while being completely devoid of antiviral activity against a wide range of DNA viruses. The derivatization of the phosphonic acid functionality of FPMPs with a diamyl aspartate phenoxyamidate group led to a novel generation of compounds that not only demonstrate drastically improved antiretroviral potency but also are characterized by an expanded spectrum of activity that also covers hepatitis B and herpes viruses. The best compound, the (S)-FPMPA amidate prodrug, exerts anti-HIV-1 activity in TZM-bl and peripheral blood mononuclear cells at low nanomolar concentrations and displays excellent potency against hepatitis B virus (HBV) and varicella-zoster virus (VZV). This prodrug is stable in acid and human plasma media, but it is efficiently processed in human liver microsomes with a half-life of 2 min. The (R) isomeric guanine derivative emerged as a selectively active anti-HIV and anti-HBV inhibitor, while being nontoxic to human hepatoblastoma cells. Notably, the pyrimidine containing prodrug (S)-Asp-FPMPC is the only congener within this series to demonstrate micromolar antihuman cytomegalovirus (HCMV) potency.
|
Inhibition of hepatitis B virus capsid assembly infected in human HepG2.215 cells assessed as reduction in viral DNA replication measured on day 7 by real time PCR analysis
|
Hepatitis B virus
|
241.5
nM
|
|
Journal : Bioorg Med Chem
Title : Discovery of hepatitis B virus capsid assembly inhibitors leading to a heteroaryldihydropyrimidine based clinical candidate (GLS4).
Year : 2017
Volume : 25
Issue : 3
First Page : 1042
Last Page : 1056
Authors : Ren Q, Liu X, Luo Z, Li J, Wang C, Goldmann S, Zhang J, Zhang Y.
Abstract : Inhibition of hepatitis B virus (HBV) capsid assembly is a novel strategy for the development of chronic hepatitis B (CHB) therapeutics. Herein we described our lead optimization studies including the synthesis, molecular docking studies and structure-activity relationship (SAR) studies of a series of novel heteroaryldihydropyrimidine (HAP) inhibitors of HBV capsid assembly inhibitors, and the discovery of a potent inhibitor of HBV capsid assembly of GLS4 (ethyl 4-[2-bromo-4-fluorophenyl]-6-[morpholino-methyl]-2-[2-thiazolyl]-1,4-dihydro-pyrimidine-5-carboxylate) which is now in clinical phase 2. GLS4 demonstrated potent inhibitory activities in HBV HepG2.2.15 cell assay with an EC50 value of 1nM, and it also exhibited high potency against various drug-resistant HBV viral strains with EC50 values in the range of 10-20nM, more potent than the typical HBV polymerase inhibitors such as lamivudine, telbivudine, and entecavir. Pharmacokinetic profiles of GLS4 were favorable and safety evaluation including acute toxicity and repeated toxicity study indicated that GLS4 was safe enough to support clinical experiments in human.
|
Antiviral activity against HSV
|
unidentified herpesvirus
|
105.0
ug.mL-1
|
|
Journal : Eur J Med Chem
Title : Polypharmacology in HIV inhibition: can a drug with simultaneous action against two relevant targets be an alternative to combination therapy?
Year : 2018
Volume : 150
First Page : 206
Last Page : 227
Authors : de Castro S, Camarasa MJ.
Abstract : HIV infection still has a serious health and socio-economical impact and is one of the primary causes of morbidity and mortality all over the world. HIV infection and the AIDS pandemic are still matters of great concern, especially in less developed countries where the access to highly active antiretroviral therapy (HAART) is limited. Patient compliance is another serious drawback. Nowadays, HAART is the treatment of choice although it is not the panacea. Despite the fact that it suppresses viral replication at undetectable viral loads and prevents progression of HIV infection into AIDS HAART has several pitfalls, namely, long-term side-effects, drug resistance development, emergence of drug-resistant viruses, low compliance and the intolerance of some patients to these drugs. Moreover, another serious health concern is the event of co-infection with more than one pathogen at the same time (e.g. HIV and HCV, HBV, herpes viruses, etc). Currently, the multi-target drug approach has become an exciting strategy to address complex diseases and overcome drug resistance development. Such multifunctional molecules combine in their structure pharmacophores that may simultaneously interfere with multiple targets and their use may eventually be more safe and efficacious than that involving a mixture of separate molecules because of avoidance or delay of drug resistance, lower incidence of unwanted drug-drug interactions and improved compliance. In this review we focus on multifunctional molecules with dual activity against different targets of the HIV life cycle or able to block replication, not only of HIV but also of other viruses that are often co-pathogens of HIV. The different approaches are documented by selected examples.
|
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
|
-14.56
%
|
|
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.
|
Antiviral activity against HIV1 infected in human PBMC assessed as inhibition of viral replication by measuring reverse transcriptase activity in cell supernatant preincubated with cells followed by viral infection measured after 7 days by radioactive incorporation polymerization assay
|
Human immunodeficiency virus 1
|
319.0
nM
|
|
Journal : J Med Chem
Title : Reduction Sensitive Lipid Conjugates of Tenofovir: Synthesis, Stability, and Antiviral Activity.
Year : 2016
Volume : 59
Issue : 15
First Page : 7097
Last Page : 7110
Authors : Giesler KE, Marengo J, Liotta DC.
Abstract : The therapeutic value of numerous small molecules hinges on their ability to permeate the plasma membrane. This is particularly true for tenofovir (TFV), adefovir, and other antiviral nucleosides that demonstrate potent antiviral activity but poor bioavailability. Using TFV as a model substrate, we hybridized two disparate prodrug strategies to afford novel reduction-sensitive lipid conjugates of TFV that exhibit subnanomolar activity toward HIV-1 and are stable in human plasma for more than 24 h with a therapeutic index approaching 30000. These compounds significantly rival the clinically approved formulation of TFV and revitalize the potential of disulfide-bearing prodrugs which have seen limited in vitro and in vivo success since their debut over 20 years ago. We further demonstrate the utility of these conjugates as a tool to indirectly probe the enzymatic hydrolysis of phosphonomonoesters that may further advance the development of other prodrug strategies for nucleosides, peptides, and beyond.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
18.78
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
34.82
%
|
|
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.
|
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
|
0.02
%
|
|
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
|
-0.07
%
|
|
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
|
0.02
%
|
|
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
|
-0.07
%
|
|
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.
|
Antiviral activity against HBV infected in human HepAD38 cells assessed as reduction in viral DNA levels incubated for 6 days by PCR analysis
|
Hepatitis B virus
|
10.0
nM
|
|
Journal : J Med Chem
Title : Discovery of (1H-Pyrazolo[3,4-c]pyridin-5-yl)sulfonamide Analogues as Hepatitis B Virus Capsid Assembly Modulators by Conformation Constraint.
Year : 2020
Volume : 63
Issue : 11
First Page : 6066
Last Page : 6089
Authors : Wang C, Pei Y, Wang L, Li S, Jiang C, Tan X, Dong Y, Xiang Y, Ma Y, Liu G.
Abstract : Hepatitis B virus (HBV) capsid assembly modulators (CAMs) have been suggested to be effective anti-HBV agents in both preclinical and clinical studies. In addition to blocking HBV replication, CAMs could reduce the formation of covalently closed circular DNA (cccDNA), which accounts for the persistence of HBV infection. Here, we describe the discovery of (1H-indazole-5-yl)sulfonamides and (1H-pyrazolo[3,4-c]pyridin-5-yl)sulfonamides as new CAM chemotypes by constraining the conformation of the sulfamoylbenzamide derivatives. Lead optimization resulted in compound 56 with an EC50 value of 0.034 μM and good metabolic stability in mouse liver microsomes. To increase the solubility, the amino acid prodrug (65) and its citric acid salt (67) were prepared. Compound 67 dose dependently inhibited HBV replication in a hydrodynamic injection-based mouse model of HBV infection, while 56 did not show in vivo anti-HBV activity, likely owing to its suboptimal solubility. This class of compounds may serve as a starting point to develop novel anti-HBV drugs.
|
Antiviral activity against HBV infected in human HepG2.A64 cells containing reverse transcriptase L180M/T184L/M204V mutant assessed as reduction in viral replication incubated for 6 days by PCR analysis
|
Hepatitis B virus
|
840.0
nM
|
|
Journal : J Med Chem
Title : Discovery of (1H-Pyrazolo[3,4-c]pyridin-5-yl)sulfonamide Analogues as Hepatitis B Virus Capsid Assembly Modulators by Conformation Constraint.
Year : 2020
Volume : 63
Issue : 11
First Page : 6066
Last Page : 6089
Authors : Wang C, Pei Y, Wang L, Li S, Jiang C, Tan X, Dong Y, Xiang Y, Ma Y, Liu G.
Abstract : Hepatitis B virus (HBV) capsid assembly modulators (CAMs) have been suggested to be effective anti-HBV agents in both preclinical and clinical studies. In addition to blocking HBV replication, CAMs could reduce the formation of covalently closed circular DNA (cccDNA), which accounts for the persistence of HBV infection. Here, we describe the discovery of (1H-indazole-5-yl)sulfonamides and (1H-pyrazolo[3,4-c]pyridin-5-yl)sulfonamides as new CAM chemotypes by constraining the conformation of the sulfamoylbenzamide derivatives. Lead optimization resulted in compound 56 with an EC50 value of 0.034 μM and good metabolic stability in mouse liver microsomes. To increase the solubility, the amino acid prodrug (65) and its citric acid salt (67) were prepared. Compound 67 dose dependently inhibited HBV replication in a hydrodynamic injection-based mouse model of HBV infection, while 56 did not show in vivo anti-HBV activity, likely owing to its suboptimal solubility. This class of compounds may serve as a starting point to develop novel anti-HBV drugs.
|
Antiviral activity against HBV infected in human HepG2.2.15 cells assessed as reduction in viral DNA levels incubated for 6 days by PCR analysis
|
Hepatitis B virus
|
0.064
nM
|
|
Journal : J Med Chem
Title : Discovery of (1H-Pyrazolo[3,4-c]pyridin-5-yl)sulfonamide Analogues as Hepatitis B Virus Capsid Assembly Modulators by Conformation Constraint.
Year : 2020
Volume : 63
Issue : 11
First Page : 6066
Last Page : 6089
Authors : Wang C, Pei Y, Wang L, Li S, Jiang C, Tan X, Dong Y, Xiang Y, Ma Y, Liu G.
Abstract : Hepatitis B virus (HBV) capsid assembly modulators (CAMs) have been suggested to be effective anti-HBV agents in both preclinical and clinical studies. In addition to blocking HBV replication, CAMs could reduce the formation of covalently closed circular DNA (cccDNA), which accounts for the persistence of HBV infection. Here, we describe the discovery of (1H-indazole-5-yl)sulfonamides and (1H-pyrazolo[3,4-c]pyridin-5-yl)sulfonamides as new CAM chemotypes by constraining the conformation of the sulfamoylbenzamide derivatives. Lead optimization resulted in compound 56 with an EC50 value of 0.034 μM and good metabolic stability in mouse liver microsomes. To increase the solubility, the amino acid prodrug (65) and its citric acid salt (67) were prepared. Compound 67 dose dependently inhibited HBV replication in a hydrodynamic injection-based mouse model of HBV infection, while 56 did not show in vivo anti-HBV activity, likely owing to its suboptimal solubility. This class of compounds may serve as a starting point to develop novel anti-HBV drugs.
|
Antiviral activity against HIV1 infected in human PBMC assessed as reduction in viral replication incubated for 7 days by radioactive incorporation polymerization assay based reverse transcriptase activity detection method
|
Human immunodeficiency virus 1
|
320.0
nM
|
|
Journal : J Med Chem
Title : Next-Generation Reduction Sensitive Lipid Conjugates of Tenofovir: Antiviral Activity and Mechanism of Release.
Year : 2016
Volume : 59
Issue : 22
First Page : 10244
Last Page : 10252
Authors : Giesler KE,Liotta DC
Abstract : The pharmacokinetic properties of tenofovir (TFV) and other charged nucleoside analogues are dramatically improved upon conjugation to a lipid prodrug. We previously prepared reduction-sensitive lipid conjugates of TFV that demonstrate superior antiviral activity compared to other lipid conjugates including the clinically approved formulation, tenofovir disoproxil fumarate (TDF). In continuation of that work, we have synthesized next-generation conjugates with reduced cytotoxicity that retain potent antiviral activity against HIV-1 and HBV with a therapeutic index >100000 for our most potent conjugate. We also show that disulfide reduction is not responsible for prodrug cleavage unless 3-exo-tet intramolecular cyclization can occur, suggesting that enzymatic hydrolysis is predominantly responsible for activity of our prodrugs in vitro.
