title: Identification and Characterization of BMS-955176, a Second-Generation HIV-1 Maturation Inhibitor with Improved Potency, Antiviral Spectrum, and Gag Polymorphic Coverage.
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.
authors.affiliation: Bristol-Myers Squibb, Research and Development, Department of Virology, Wallingford, Connecticut, USA.
authors.forename: Beata
authors.initials: B
authors.lastname: Nowicka-Sans
authors.affiliation: Bristol-Myers Squibb, Research and Development, Department of Virology, Wallingford, Connecticut, USA.
authors.forename: Tricia
authors.initials: T
authors.lastname: Protack
authors.affiliation: Bristol-Myers Squibb, Research and Development, Department of Virology, Wallingford, Connecticut, USA.
authors.forename: Zeyu
authors.initials: Z
authors.lastname: Lin
authors.affiliation: Bristol-Myers Squibb, Research and Development, Department of Virology, Wallingford, Connecticut, USA.
authors.forename: Zhufang
authors.initials: Z
authors.lastname: Li
authors.affiliation: Bristol-Myers Squibb, Research and Development, Department of Virology, Wallingford, Connecticut, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Bristol-Myers Squibb, Research and Development, Department of Virology, Wallingford, Connecticut, USA.
authors.forename: Yongnian
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Bristol-Myers Squibb, Research and Development, Department of Virology, Wallingford, Connecticut, USA.
authors.forename: Himadri
authors.initials: H
authors.lastname: Samanta
authors.affiliation: Bristol-Myers Squibb, Research and Development, Department of Virology, Wallingford, Connecticut, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Terry
authors.affiliation: Bristol-Myers Squibb, Research and Development, Department of Discovery Chemistry, Wallingford, Connecticut, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Bristol-Myers Squibb, Research and Development, Department of Discovery Chemistry, Wallingford, Connecticut, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Bristol-Myers Squibb, Research and Development, Department of Discovery Chemistry, Wallingford, Connecticut, USA.
authors.forename: Ny
authors.initials: N
authors.lastname: Sin
authors.affiliation: Bristol-Myers Squibb, Research and Development, Department of Discovery Chemistry, Wallingford, Connecticut, USA.
authors.forename: Sing-Yuen
authors.initials: SY
authors.lastname: Sit
authors.affiliation: Bristol-Myers Squibb, Research and Development, Department of Discovery Chemistry, Wallingford, Connecticut, USA.
authors.forename: Jacob J
authors.initials: JJ
authors.lastname: Swidorski
authors.affiliation: Bristol-Myers Squibb, Research and Development, Department of Discovery Chemistry, Wallingford, Connecticut, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.affiliation: Bristol-Myers Squibb, Research and Development, Department of Discovery Chemistry, Wallingford, Connecticut, USA.
authors.forename: Brian L
authors.initials: BL
authors.lastname: Venables
authors.affiliation: Bristol-Myers Squibb, Research and Development, Department of Genomics, Wallingford, Connecticut, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Healy
authors.affiliation: Bristol-Myers Squibb, Research and Development, Department of Discovery Chemistry, Wallingford, Connecticut, USA.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Meanwell
authors.affiliation: Bristol-Myers Squibb, Research and Development, Department of Virology, Wallingford, Connecticut, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Cockett
authors.affiliation: Bristol-Myers Squibb, Research and Development, Department of Preclinical Optimization, Wallingford, Connecticut, USA.
authors.forename: Umesh
authors.initials: U
authors.lastname: Hanumegowda
authors.affiliation: Bristol-Myers Squibb, Research and Development, Department of Discovery Chemistry, Wallingford, Connecticut, USA.
authors.forename: Alicia
authors.initials: A
authors.lastname: Regueiro-Ren
authors.affiliation: Bristol-Myers Squibb, Research and Development, Department of Virology, Wallingford, Connecticut, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Krystal
authors.affiliation: Bristol-Myers Squibb, Research and Development, Department of Virology, Wallingford, Connecticut, USA Ira.B.Dicker@viivhealthcare.com.
authors.forename: Ira B
authors.initials: IB
authors.lastname: Dicker
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D024882:Drug Resistance, Viral / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D013386:Succinates / Q000494:pharmacology; D014315:Triterpenes / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000037:antagonists & inhibitors*; D053978:Pentacyclic Triterpenes
chemical_list: D019380:Anti-HIV Agents; D013386:Succinates; D014315:Triterpenes; D054301:gag Gene Products, Human Immunodeficiency Virus; C479935:bevirimat; D053978:Pentacyclic Triterpenes