Discovery of BMS-955176, a Second Generation HIV-1 Maturation Inhibitor with Broad Spectrum Antiviral Activity

Regueiro‐Ren, Alicia; Liu, Zheng; Chen, Yan; Sin, Nancy L.; Sit, Sing‐Yuen; Swidorski, Jacob J.; Chen, Jie; Venables, Brian L.; Zhu, Juliang; Nowicka-Sans, Beata; Protack, Tricia; Lin, Zheng‐Zhe; Terry, Brian; Samanta, Himadri; Zhang, Sharon; Li, Zhufang; Beno, Brett R.; Huang, Xiaohua; Rahematpura, Sandhya; Parker, Dawn D.; Haskell, Roy; Jenkins, Susan; Santone, Kenneth S.; Cockett, Mark I.; Krystal, Mark; Meanwell, Nicholas A.; Hanumegowda, Umesh; Dicker, Ira B.

doi:10.1021/acsmedchemlett.6b00010

Cited by 49 publications

(69 citation statements)

References 15 publications

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“…Although its development was stopped, BVM provided the clinical proof of concept that MIs might be an effective alternative for HIV-1 infection management. Recently, second-generation of BVM derivatives (Qian et al, 2010(Qian et al, , 2012Dang et al, 2013;Tang et al, 2014;Urano et al, 2015Urano et al, , 2018Liu et al, 2016;Nowicka-Sans et al, 2016;Regueiro-Ren et al, 2016;Swidorski et al, 2016) have been developed to significantly increase the pan-genotypic coverage (Wang et al, 2015;Tang et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Insight into the mechanism of action of EP-39, a bevirimat derivative that inhibits HIV-1 maturation

et al. 2019

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Maturation of human immunodeficiency virus type 1 (HIV-1) particles is a key step for viral infectivity. This process can be blocked using maturation inhibitors (MIs) that affect the cleavage of the capsid-spacer peptide 1 (CA-SP1) junction. Here, we investigated the mechanisms underlying the activity of EP-39, a bevirimat (BVM) derivative with better hydrosolubility. To this aim, we selected in vitro EP-39-and BVM-resistant mutants. We found that EP-39-resistant viruses have four mutations within the CA domain (CA-A194T, CA-T200N, CA-V230I, and CA-V230A) and one in the first residue of SP1 (SP1-A1V). We also identified six mutations that confer BVM resistance (CA-A194T, CA-L231F, CA-L231M, SP1-A1V, SP1-S5N and SP1-V7A). To characterize the EP-39 and BVM-resistant mutants, we studied EP-39 effects on mutant virus replication and performed a biochemical analysis with both MIs. We observed common and distinct characteristics, suggesting that, although EP-39 and BVM share the same chemical skeleton, they could interact in a different way with the Gag polyprotein precursor (Pr55Gag). Using an in silico approach, we observed that EP-39 and BVM present different predicted positions on the hexameric crystal structure of the CA CTD-SP1 Gag fragment. To clearly understand the relationship between assembly and maturation, we investigated the impact of all identified mutations on virus assembly by expressing Pr55Gag mutants. Finally, using NMR, we have shown that the interaction of EP-39 with a peptide carrying the SP1-A1V mutation (CA-SP1(A1V)-NC) is almost suppressed in comparison with the wild type peptide. These results suggest that EP-39 and BVM could interact differently with the Pr55Gag lattice and that the mutation of the first SP1 residue induces a loss of interaction between Pr55Gag and EP-39.

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Section: Introductionmentioning

confidence: 99%

Insight into the mechanism of action of EP-39, a bevirimat derivative that inhibits HIV-1 maturation

et al. 2019

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“…However, polymorphisms in the QVT motif, in particular SP1-V7A, reduced the susceptibility of HIV-1 to BVM (26-28). To overcome this reduced potency elicited by SP1 polymorphisms, second-generation MIs are being developed by our group and others (29)(30)(31)(32)(33)(34)(35)(36). These BVM analogs display marked improvements in potency against both consensus clade B isolates (e.g., NL4-3) and primary clinical isolates from multiple HIV-1 subtypes.…”

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confidence: 99%

Resistance to Second-Generation HIV-1 Maturation Inhibitors

Urano

Timilsina

Kaplan

et al. 2019

J Virol

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A betulinic acid-based compound, bevirimat (BVM), inhibits HIV-1 maturation by blocking a late step in protease-mediated Gag processing: the cleavage of the capsid-spacer peptide 1 (CA-SP1) intermediate to mature CA. Previous studies showed that mutations conferring resistance to BVM cluster around the CA-SP1 cleavage site. Single amino acid polymorphisms in the SP1 region of Gag and the C terminus of CA reduced HIV-1 susceptibility to BVM, leading to the discontinuation of BVM’s clinical development. We recently reported a series of “second-generation” BVM analogs that display markedly improved potency and breadth of activity relative to the parent molecule. Here, we demonstrate that viral clones bearing BVM resistance mutations near the C terminus of CA are potently inhibited by second-generation BVM analogs. We performedde novoselection experiments to identify mutations that confer resistance to these novel compounds. Selection experiments with subtype B HIV-1 identified an Ala-to-Val mutation at SP1 residue 1 and a Pro-to-Ala mutation at CA residue 157 within the major homology region (MHR). In selection experiments with subtype C HIV-1, we identified mutations at CA residue 230 (CA-V230M) and SP1 residue 1 (SP1-A1V), residue 5 (SP1-S5N), and residue 10 (SP1-G10R). The positions at which resistance mutations arose are highly conserved across multiple subtypes of HIV-1. We demonstrate that the mutations confer modest to high-level maturation inhibitor resistance. In most cases, resistance was not associated with a detectable increase in the kinetics of CA-SP1 processing. These results identify mutations that confer resistance to second-generation maturation inhibitors and provide novel insights into the mechanism of resistance.IMPORTANCEHIV-1 maturation inhibitors are a class of small-molecule compounds that block a late step in the viral protease-mediated processing of the Gag polyprotein precursor, the viral protein responsible for the formation of virus particles. The first-in-class HIV-1 maturation inhibitor bevirimat was highly effective in blocking HIV-1 replication, but its activity was compromised by naturally occurring sequence polymorphisms within Gag. Recently developed bevirimat analogs, referred to as “second-generation” maturation inhibitors, overcome this issue. To understand more about how these second-generation compounds block HIV-1 maturation, here we selected for HIV-1 mutants that are resistant to these compounds. Selections were performed in the context of two different subtypes of HIV-1. We identified a small set of mutations at highly conserved positions within the capsid and spacer peptide 1 domains of Gag that confer resistance. Identification and analysis of these maturation inhibitor-resistant mutants provide insights into the mechanisms of resistance to these compounds.

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“…For example, in the case of bevirimat, a well-studied HIV-1 maturation inhibitor that blocks the cleavage between CA and p2, even a partial blockage at this cleavage site can elicit a significant antiviral effect (83)(84)(85)(86)(87).…”

Section: Discussionmentioning

confidence: 99%

Conserved Interaction of Lentiviral Vif Molecules with HIV-1 Gag and Differential Effects of Species-Specific Vif on Virus Production

Zheng

Ling

et al. 2017

J Virol

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Discovery of BMS-955176, a Second Generation HIV-1 Maturation Inhibitor with Broad Spectrum Antiviral Activity

Cited by 49 publications

References 15 publications

Insight into the mechanism of action of EP-39, a bevirimat derivative that inhibits HIV-1 maturation

Insight into the mechanism of action of EP-39, a bevirimat derivative that inhibits HIV-1 maturation

Resistance to Second-Generation HIV-1 Maturation Inhibitors

Conserved Interaction of Lentiviral Vif Molecules with HIV-1 Gag and Differential Effects of Species-Specific Vif on Virus Production

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