Inhibitors of HIV-1 maturation: Development of structure–activity relationship for C-28 amides based on C-3 benzoic acid-modified triterpenoids

Swidorski, Jacob J.; Liu, Zheng; Sit, Sing‐Yuen; Chen, Jie; Chen, Yan; Sin, Nancy L.; Venables, Brian L.; Parker, Dawn D.; Nowicka-Sans, Beata; Terry, Brian; Protack, Tricia; Rahematpura, Sandhya; Hanumegowda, Umesh; Jenkins, Susan; Krystal, Mark; Dicker, Ira B.; Meanwell, Nicholas A.; Regueiro‐Ren, Alicia

doi:10.1016/j.bmcl.2016.03.019

Cited by 33 publications

(51 citation statements)

References 15 publications

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“…[19–21] BMS-955176 was identified as a clinical candidate with improved potency against viruses containing these polymorphic substitutions, low human serum binding and excellent PK properties [35–38, 40, 55] BMS-955176 (Fig 1) retains potent activity toward these polymorphic variants in vitro and was active in a Ph2a POC study[41–43] As shown in Table 1,[40] BMS-955176 is 5.4-fold more potent than BVM toward WT virus, and polymorphic viruses retain sensitivity to BMS-955176, with FC values (EC 50 /WT EC 50 ) between 1- and 6.8-fold. [35, 36, 40] The protease inhibitor nelfinavir was used as a control, which exhibits similar antiviral characteristics towards all the polymorphic viruses.…”

Section: Resultsmentioning

confidence: 99%

Mechanistic Studies and Modeling Reveal the Origin of Differential Inhibition of Gag Polymorphic Viruses by HIV-1 Maturation Inhibitors

et al. 2016

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HIV-1 maturation inhibitors (MIs) disrupt the final step in the HIV-1 protease-mediated cleavage of the Gag polyprotein between capsid p24 capsid (CA) and spacer peptide 1 (SP1), leading to the production of infectious virus. BMS-955176 is a second generation MI with improved antiviral activity toward polymorphic Gag variants compared to a first generation MI bevirimat (BVM). The underlying mechanistic reasons for the differences in polymorphic coverage were studied using antiviral assays, an LC/MS assay that quantitatively characterizes CA/SP1 cleavage kinetics of virus like particles (VLPs) and a radiolabel binding assay to determine VLP/MI affinities and dissociation kinetics. Antiviral assay data indicates that BVM does not achieve 100% inhibition of certain polymorphs, even at saturating concentrations. This results in the breakthrough of infectious virus (partial antagonism) regardless of BVM concentration. Reduced maximal percent inhibition (MPI) values for BVM correlated with elevated EC50 values, while rates of HIV-1 protease cleavage at CA/SP1 correlated inversely with the ability of BVM to inhibit HIV-1 Gag polymorphic viruses: genotypes with more rapid CA/SP1 cleavage kinetics were less sensitive to BVM. In vitro inhibition of wild type VLP CA/SP1 cleavage by BVM was not maintained at longer cleavage times. BMS-955176 exhibited greatly improved MPI against polymorphic Gag viruses, binds to Gag polymorphs with higher affinity/longer dissociation half-lives and exhibits greater time-independent inhibition of CA/SP1 cleavage compared to BVM. Virological (MPI) and biochemical (CA/SP1 cleavage rates, MI-specific Gag affinities) data were used to create an integrated semi-quantitative model that quantifies CA/SP1 cleavage rates as a function of both MI and Gag polymorph. The model outputs are in accord with in vitro antiviral observations and correlate with observed in vivo MI efficacies. Overall, these findings may be useful to further understand antiviral profiles and clinical responses of MIs at a basic level, potentially facilitating further improvements to MI potency and coverage.

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Section: Resultsmentioning

confidence: 99%

Mechanistic Studies and Modeling Reveal the Origin of Differential Inhibition of Gag Polymorphic Viruses by HIV-1 Maturation Inhibitors

et al. 2016

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“…The first characterized maturation inhibitor was bevirimat (BVM), which acts by preventing PR cleavage between residues L363 and A364 in the junction helix formed by the C-terminal domain of CA and SP1 spacer peptide, thereby stabilizing the immature lattice 10 11 However, the mechanism by which BVM stabilizes the immature lattice is unclear. Although BVM entered clinical trials, efficacy was thwarted by the presence of preexisting resistant viruses containing SP1 polymorphisms 12,13 . Second generation maturation inhibitors have improved resistance profiles 14 15 , but rational drug development has been impeded by a lack of high-resolution structural data on maturation inhibitor binding to Gag.…”

mentioning

confidence: 99%

MicroED Structures of HIV-1 Gag CTD-SP1 Reveal Binding Interactions with the Maturation Inhibitor Bevirimat

Purdy

Shi

Chrustowicz

et al. 2017

Preprint

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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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Inhibitors of HIV-1 maturation: Development of structure–activity relationship for C-28 amides based on C-3 benzoic acid-modified triterpenoids

Cited by 33 publications

References 15 publications

Mechanistic Studies and Modeling Reveal the Origin of Differential Inhibition of Gag Polymorphic Viruses by HIV-1 Maturation Inhibitors

Mechanistic Studies and Modeling Reveal the Origin of Differential Inhibition of Gag Polymorphic Viruses by HIV-1 Maturation Inhibitors

MicroED Structures of HIV-1 Gag CTD-SP1 Reveal Binding Interactions with the Maturation Inhibitor Bevirimat

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

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