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.
Highlights
BMS-955176 is a second-generation human immunodeficiency virus type 1 (HIV-1) maturation inhibitor (MI)
New drugs with novel mechanisms of action (MOAs) that can be used as part of a preferred regimen should still have a strong role to play in combination antiretroviral therapy regimens if they can be used as part of a once-a-day preferred regimen, have high genetic barriers to the development of resistance in the context of fixed-dose combinations and regimens, have improved safety over current agents, and have minimal drug-drug interactions
A structure-activity relationship (SAR) strategy was driven using a panel of BVM-resistant Gag polymorphic site-directed mutant (SDM) viruses, including V362I, V370A, and V370⌬ mutants, with concomitant evaluation of serum effects toward WT virus
Summary
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 ϳ50% of subjects had viruses with reduced susceptibility associated with naturally occurring polymorphisms in Gag near the site of MI action. It occurs through a series of HIV-1 proteasemediated cleavage reactions, with the last event occurring within the structural polyprotein Gag (Fig. 1), at a site between the capsid (CA) and spacer peptide 1 (SP1) This cleavage triggers a structural rearrangement, transforming the immature virus particle to a mature virion, characterized by an electron-dense conical core. Other maturation inhibitors (MIs) structurally related to BVM [23,24,25] have been disclosed, with one reportedly active toward V370A, a key BVMresistant polymorphism [26, 27], while another, more structurally diverse analog of betulinic acid entered phase 1 clinical trials [28]. Another MI, PF-46396, is structurally distinct from BVM [29, 30], with a resistance profile that overlaps but is nonidentical to that of BVM [31]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
