C-3 benzoic acid derivatives of C-3 deoxybetulinic acid and deoxybetulin as HIV-1 maturation inhibitors

Liu, Zheng; Swidorski, Jacob J.; Nowicka-Sans, Beata; Terry, Brian; Protack, Tricia; Lin, Zheng‐Zhe; Samanta, Himadri; Zhang, Sharon; Li, Zhufang; Parker, Dawn D.; Rahematpura, Sandhya; Jenkins, Susan; Beno, Brett R.; Krystal, Mark; Meanwell, Nicholas A.; Dicker, Ira B.; Regueiro‐Ren, Alicia

doi:10.1016/j.bmc.2016.03.001

Cited by 26 publications

(52 citation statements)

References 45 publications

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“…By comparison, BVM is >100-fold less active toward both V370A/ΔT371 and ΔV370-containing viruses. An early BMS compound in the series leading to the identification of BMS-955176 was BMS-1 (Fig 1),[37] with an antiviral profile similar to BVM. It was included in this study to determine if the results were able to be generalized beyond BVM and BMS-955176.…”

Section: Resultsmentioning

confidence: 99%

“…[37] Similar to BVM, the first generation BMS-1 (FC values similar to BVM, Table 1) exhibits a high MPI against wild type virus (97.0 +/- 0.5), but only partially inhibits V362I and V370A viruses (MPIs = 71.4 +/- 5.4 and 63.2 +/- 4.7, respectively) and does not inhibit ΔV370 containing virus (MPI = 3.7 +/- 2.9) (Fig 2B and Table 2). By comparison, BMS-955176 exhibits high MPI values of 100 +/- 0.4, 98.2 +/- 1.3, 93.8 +/- 1.8 and 91.9 +/- 4.4 for WT, V370A, V362I and the ΔV370 containing viruses, respectively (Fig 2C and Table 2).…”

Section: Resultsmentioning

confidence: 99%

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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%

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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“…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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“…As the first step in our study of this chemotype, we explored changes to the succinic acid-based side chain at C-3, a moiety that appeared to have largely been accepted as a pharmacophoric element, with a view to revealing key aspects of the topography of the carboxylic acid while providing new opportunities for structural modification. 19,20 The benzoic acid derivative 3 emerged very quickly from that effort, exhibiting good antiviral activity against wild-type (WT) virus, a modest 7-fold shift in the presence of HS, and good oral exposure in rats (Table 1). The para-substitution pattern in 3 was critical for antiviral activity.…”

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confidence: 99%

“…However, potency against Gag V370A, the most prevalent polymorphism in the region of Gag associated with MI activity, was lacking. 19 Attention was then directed toward derivatization of the C-28 position of 3, where an extensive series of analogues were prepared that incorporated a wide range of functionality. Amides such as 4, incorporating a basic side chain, provided excellent potency against both WT and V370A viruses, while maintaining a low human serum shift (∼4-fold).…”

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

Regueiro‐Ren

Liu

Chen

et al. 2016

ACS Med. Chem. Lett.

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HIV-1 maturation inhibition (MI) has been clinically validated as an approach to the control of HIV-1 infection. However, identifying an MI with both broad polymorphic spectrum coverage and good oral exposure has been challenging. Herein, we describe the design, synthesis, and preclinical characterization of a potent, orally active, second generation HIV-1 MI, BMS-955176 (2), which is currently in Phase IIb clinical trials as part of a combination antiretroviral regimen.

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C-3 benzoic acid derivatives of C-3 deoxybetulinic acid and deoxybetulin as HIV-1 maturation inhibitors

Cited by 26 publications

References 45 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

Resistance to Second-Generation HIV-1 Maturation Inhibitors

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

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