Identification and Characterization of BMS-955176, a Second-Generation HIV-1 Maturation Inhibitor with Improved Potency, Antiviral Spectrum, and Gag Polymorphic Coverage
BMS-955176 is a second-generation human immunodeficiency virus type 1 (HIV-1) maturation inhibitor (MI). A first-generation MI, bevirimat, showed clinical efficacy in early-phase studies, but ∼50% of subjects had viruses with reduced susceptibility associated with naturally occurring polymorphisms i...
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| Vydáno v: | Antimicrobial agents and chemotherapy Ročník 60; číslo 7; s. 3956 |
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| Médium: | Journal Article |
| Jazyk: | angličtina |
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01.07.2016
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| ISSN: | 1098-6596, 1098-6596 |
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| Abstract | BMS-955176 is a second-generation human immunodeficiency virus type 1 (HIV-1) maturation inhibitor (MI). A first-generation MI, bevirimat, showed clinical efficacy in early-phase studies, but ∼50% of subjects had viruses with reduced susceptibility associated with naturally occurring polymorphisms in Gag near the site of MI action. MI potency was optimized using a panel of engineered reporter viruses containing site-directed polymorphic changes in Gag that reduce susceptibility to bevirimat (including V362I, V370A/M/Δ, and T371A/Δ), leading incrementally to the identification of BMS-955176. BMS-955176 exhibits potent activity (50% effective concentration [EC50], 3.9 ± 3.4 nM [mean ± standard deviation]) toward a library (n = 87) of gag/pr recombinant viruses representing 96.5% of subtype B polymorphic Gag diversity near the CA/SP1 cleavage site. BMS-955176 exhibited a median EC50 of 21 nM toward a library of subtype B clinical isolates assayed in peripheral blood mononuclear cells (PBMCs). Potent activity was maintained against a panel of reverse transcriptase, protease, and integrase inhibitor-resistant viruses, with EC50s similar to those for the wild-type virus. A 5.4-fold reduction in EC50 occurred in the presence of 40% human serum plus 27 mg/ml of human serum albumin (HSA), which corresponded well to an in vitro measurement of 86% human serum binding. Time-of-addition and pseudotype reporter virus studies confirm a mechanism of action for the compound that occurs late in the virus replication cycle. BMS-955176 inhibits HIV-1 protease cleavage at the CA/SP1 junction within Gag in virus-like particles (VLPs) and in HIV-1-infected cells, and it binds reversibly and with high affinity to assembled Gag in purified HIV-1 VLPs. Finally, in vitro combination studies showed no antagonistic interactions with representative antiretrovirals (ARVs) of other mechanistic classes. In conclusion, BMS-955176 is a second-generation MI with potent in vitro anti-HIV-1 activity and a greatly improved preclinical profile compared to that of bevirimat. |
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| AbstractList | BMS-955176 is a second-generation human immunodeficiency virus type 1 (HIV-1) maturation inhibitor (MI). A first-generation MI, bevirimat, showed clinical efficacy in early-phase studies, but ∼50% of subjects had viruses with reduced susceptibility associated with naturally occurring polymorphisms in Gag near the site of MI action. MI potency was optimized using a panel of engineered reporter viruses containing site-directed polymorphic changes in Gag that reduce susceptibility to bevirimat (including V362I, V370A/M/Δ, and T371A/Δ), leading incrementally to the identification of BMS-955176. BMS-955176 exhibits potent activity (50% effective concentration [EC50], 3.9 ± 3.4 nM [mean ± standard deviation]) toward a library (n = 87) of gag/pr recombinant viruses representing 96.5% of subtype B polymorphic Gag diversity near the CA/SP1 cleavage site. BMS-955176 exhibited a median EC50 of 21 nM toward a library of subtype B clinical isolates assayed in peripheral blood mononuclear cells (PBMCs). Potent activity was maintained against a panel of reverse transcriptase, protease, and integrase inhibitor-resistant viruses, with EC50s similar to those for the wild-type virus. A 5.4-fold reduction in EC50 occurred in the presence of 40% human serum plus 27 mg/ml of human serum albumin (HSA), which corresponded well to an in vitro measurement of 86% human serum binding. Time-of-addition and pseudotype reporter virus studies confirm a mechanism of action for the compound that occurs late in the virus replication cycle. BMS-955176 inhibits HIV-1 protease cleavage at the CA/SP1 junction within Gag in virus-like particles (VLPs) and in HIV-1-infected cells, and it binds reversibly and with high affinity to assembled Gag in purified HIV-1 VLPs. Finally, in vitro combination studies showed no antagonistic interactions with representative antiretrovirals (ARVs) of other mechanistic classes. In conclusion, BMS-955176 is a second-generation MI with potent in vitro anti-HIV-1 activity and a greatly improved preclinical profile compared to that of bevirimat.BMS-955176 is a second-generation human immunodeficiency virus type 1 (HIV-1) maturation inhibitor (MI). A first-generation MI, bevirimat, showed clinical efficacy in early-phase studies, but ∼50% of subjects had viruses with reduced susceptibility associated with naturally occurring polymorphisms in Gag near the site of MI action. MI potency was optimized using a panel of engineered reporter viruses containing site-directed polymorphic changes in Gag that reduce susceptibility to bevirimat (including V362I, V370A/M/Δ, and T371A/Δ), leading incrementally to the identification of BMS-955176. BMS-955176 exhibits potent activity (50% effective concentration [EC50], 3.9 ± 3.4 nM [mean ± standard deviation]) toward a library (n = 87) of gag/pr recombinant viruses representing 96.5% of subtype B polymorphic Gag diversity near the CA/SP1 cleavage site. BMS-955176 exhibited a median EC50 of 21 nM toward a library of subtype B clinical isolates assayed in peripheral blood mononuclear cells (PBMCs). Potent activity was maintained against a panel of reverse transcriptase, protease, and integrase inhibitor-resistant viruses, with EC50s similar to those for the wild-type virus. A 5.4-fold reduction in EC50 occurred in the presence of 40% human serum plus 27 mg/ml of human serum albumin (HSA), which corresponded well to an in vitro measurement of 86% human serum binding. Time-of-addition and pseudotype reporter virus studies confirm a mechanism of action for the compound that occurs late in the virus replication cycle. BMS-955176 inhibits HIV-1 protease cleavage at the CA/SP1 junction within Gag in virus-like particles (VLPs) and in HIV-1-infected cells, and it binds reversibly and with high affinity to assembled Gag in purified HIV-1 VLPs. Finally, in vitro combination studies showed no antagonistic interactions with representative antiretrovirals (ARVs) of other mechanistic classes. In conclusion, BMS-955176 is a second-generation MI with potent in vitro anti-HIV-1 activity and a greatly improved preclinical profile compared to that of bevirimat. BMS-955176 is a second-generation human immunodeficiency virus type 1 (HIV-1) maturation inhibitor (MI). A first-generation MI, bevirimat, showed clinical efficacy in early-phase studies, but ∼50% of subjects had viruses with reduced susceptibility associated with naturally occurring polymorphisms in Gag near the site of MI action. MI potency was optimized using a panel of engineered reporter viruses containing site-directed polymorphic changes in Gag that reduce susceptibility to bevirimat (including V362I, V370A/M/Δ, and T371A/Δ), leading incrementally to the identification of BMS-955176. BMS-955176 exhibits potent activity (50% effective concentration [EC50], 3.9 ± 3.4 nM [mean ± standard deviation]) toward a library (n = 87) of gag/pr recombinant viruses representing 96.5% of subtype B polymorphic Gag diversity near the CA/SP1 cleavage site. BMS-955176 exhibited a median EC50 of 21 nM toward a library of subtype B clinical isolates assayed in peripheral blood mononuclear cells (PBMCs). Potent activity was maintained against a panel of reverse transcriptase, protease, and integrase inhibitor-resistant viruses, with EC50s similar to those for the wild-type virus. A 5.4-fold reduction in EC50 occurred in the presence of 40% human serum plus 27 mg/ml of human serum albumin (HSA), which corresponded well to an in vitro measurement of 86% human serum binding. Time-of-addition and pseudotype reporter virus studies confirm a mechanism of action for the compound that occurs late in the virus replication cycle. BMS-955176 inhibits HIV-1 protease cleavage at the CA/SP1 junction within Gag in virus-like particles (VLPs) and in HIV-1-infected cells, and it binds reversibly and with high affinity to assembled Gag in purified HIV-1 VLPs. Finally, in vitro combination studies showed no antagonistic interactions with representative antiretrovirals (ARVs) of other mechanistic classes. In conclusion, BMS-955176 is a second-generation MI with potent in vitro anti-HIV-1 activity and a greatly improved preclinical profile compared to that of bevirimat. |
| Author | Meanwell, Nicholas A Sin, Ny Venables, Brian L Hanumegowda, Umesh Samanta, Himadri Regueiro-Ren, Alicia Chen, Yan Chen, Jie Terry, Brian Protack, Tricia Lin, Zeyu Sit, Sing-Yuen Swidorski, Jacob J Nowicka-Sans, Beata Dicker, Ira B Sun, Yongnian Krystal, Mark Zhang, Sharon Healy, Matthew Li, Zhufang Liu, Zheng Cockett, Mark |
| Author_xml | – sequence: 1 givenname: Beata surname: Nowicka-Sans fullname: Nowicka-Sans, Beata organization: Bristol-Myers Squibb, Research and Development, Department of Virology, Wallingford, Connecticut, USA – sequence: 2 givenname: Tricia surname: Protack fullname: Protack, Tricia organization: Bristol-Myers Squibb, Research and Development, Department of Virology, Wallingford, Connecticut, USA – sequence: 3 givenname: Zeyu surname: Lin fullname: Lin, Zeyu organization: Bristol-Myers Squibb, Research and Development, Department of Virology, Wallingford, Connecticut, USA – sequence: 4 givenname: Zhufang surname: Li fullname: Li, Zhufang organization: Bristol-Myers Squibb, Research and Development, Department of Virology, Wallingford, Connecticut, USA – sequence: 5 givenname: Sharon surname: Zhang fullname: Zhang, Sharon organization: Bristol-Myers Squibb, Research and Development, Department of Virology, Wallingford, Connecticut, USA – sequence: 6 givenname: Yongnian surname: Sun fullname: Sun, Yongnian organization: Bristol-Myers Squibb, Research and Development, Department of Virology, Wallingford, Connecticut, USA – sequence: 7 givenname: Himadri surname: Samanta fullname: Samanta, Himadri organization: Bristol-Myers Squibb, Research and Development, Department of Virology, Wallingford, Connecticut, USA – sequence: 8 givenname: Brian surname: Terry fullname: Terry, Brian organization: Bristol-Myers Squibb, Research and Development, Department of Virology, Wallingford, Connecticut, USA – sequence: 9 givenname: Zheng surname: Liu fullname: Liu, Zheng organization: Bristol-Myers Squibb, Research and Development, Department of Discovery Chemistry, Wallingford, Connecticut, USA – sequence: 10 givenname: Yan surname: Chen fullname: Chen, Yan organization: Bristol-Myers Squibb, Research and Development, Department of Discovery Chemistry, Wallingford, Connecticut, USA – sequence: 11 givenname: Ny surname: Sin fullname: Sin, Ny organization: Bristol-Myers Squibb, Research and Development, Department of Discovery Chemistry, Wallingford, Connecticut, USA – sequence: 12 givenname: Sing-Yuen surname: Sit fullname: Sit, Sing-Yuen organization: Bristol-Myers Squibb, Research and Development, Department of Discovery Chemistry, Wallingford, Connecticut, USA – sequence: 13 givenname: Jacob J surname: Swidorski fullname: Swidorski, Jacob J organization: Bristol-Myers Squibb, Research and Development, Department of Discovery Chemistry, Wallingford, Connecticut, USA – sequence: 14 givenname: Jie surname: Chen fullname: Chen, Jie organization: Bristol-Myers Squibb, Research and Development, Department of Discovery Chemistry, Wallingford, Connecticut, USA – sequence: 15 givenname: Brian L surname: Venables fullname: Venables, Brian L organization: Bristol-Myers Squibb, Research and Development, Department of Discovery Chemistry, Wallingford, Connecticut, USA – sequence: 16 givenname: Matthew surname: Healy fullname: Healy, Matthew organization: Bristol-Myers Squibb, Research and Development, Department of Genomics, Wallingford, Connecticut, USA – sequence: 17 givenname: Nicholas A surname: Meanwell fullname: Meanwell, Nicholas A organization: Bristol-Myers Squibb, Research and Development, Department of Discovery Chemistry, Wallingford, Connecticut, USA – sequence: 18 givenname: Mark surname: Cockett fullname: Cockett, Mark organization: Bristol-Myers Squibb, Research and Development, Department of Virology, Wallingford, Connecticut, USA – sequence: 19 givenname: Umesh surname: Hanumegowda fullname: Hanumegowda, Umesh organization: Bristol-Myers Squibb, Research and Development, Department of Preclinical Optimization, Wallingford, Connecticut, USA – sequence: 20 givenname: Alicia surname: Regueiro-Ren fullname: Regueiro-Ren, Alicia organization: Bristol-Myers Squibb, Research and Development, Department of Discovery Chemistry, Wallingford, Connecticut, USA – sequence: 21 givenname: Mark surname: Krystal fullname: Krystal, Mark organization: Bristol-Myers Squibb, Research and Development, Department of Virology, Wallingford, Connecticut, USA – sequence: 22 givenname: Ira B surname: Dicker fullname: Dicker, Ira B email: Ira.B.Dicker@viivhealthcare.com organization: Bristol-Myers Squibb, Research and Development, Department of Virology, Wallingford, Connecticut, USA Ira.B.Dicker@viivhealthcare.com |
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| SubjectTerms | Anti-HIV Agents - pharmacology Drug Resistance, Viral - genetics gag Gene Products, Human Immunodeficiency Virus - antagonists & inhibitors HIV-1 - drug effects HIV-1 - metabolism Humans Succinates - pharmacology Triterpenes - pharmacology Virus Replication - drug effects |
| Title | Identification and Characterization of BMS-955176, a Second-Generation HIV-1 Maturation Inhibitor with Improved Potency, Antiviral Spectrum, and Gag Polymorphic Coverage |
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