Identification and Characterization of BMS-955176, a Second-Generation HIV-1 Maturation Inhibitor with Improved Potency, Antiviral Spectrum, and Gag Polymorphic Coverage
Autor: | Umesh Hanumegowda, Sharon Zhang, Yan Chen, Zheng Liu, Ira B. Dicker, Zhufang Li, Sing-Yuen Sit, Ny Sin, Jacob Swidorski, Brian Terry, Himadri Samanta, Tricia Protack, Brian Lee Venables, Zeyu Lin, Yongnian Sun, Jie Chen, Beata Nowicka-Sans, Alicia Regueiro-Ren, Nicholas A. Meanwell, Matthew D. Healy, Mark Krystal, Mark I. Cockett |
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Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
Anti-HIV Agents medicine.medical_treatment 030106 microbiology Virus Replication Antiviral Agents gag Gene Products Human Immunodeficiency Virus Virus 03 medical and health sciences chemistry.chemical_compound Drug Resistance Viral medicine Humans Potency Pharmacology (medical) Pharmacology Protease biology Maturation inhibitor Succinates Virology Molecular biology Triterpenes Reverse transcriptase Integrase 030104 developmental biology Infectious Diseases Viral replication chemistry HIV-1 biology.protein Bevirimat |
Zdroj: | Antimicrobial Agents and Chemotherapy |
ISSN: | 1098-6596 0066-4804 |
Popis: | 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 [EC 50 ], 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 EC 50 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 EC 50 s similar to those for the wild-type virus. A 5.4-fold reduction in EC 50 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. |
Databáze: | OpenAIRE |
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