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Exploring Modifications of an HIV-1 Capsid Inhibitor: Design, Synthesis, and Mechanism of Action.

ABSTRACT: Recent efforts by both academic and pharmaceutical researchers have focused on the HIV-1 capsid (CA) protein as a new therapeutic target. An interprotomer pocket within the hexamer configuration of the CA, which is also a binding site for key host dependency factors, is the target of the most widely studied CA inhibitor compound PF-3450074 (PF-74). Despite its popularity, PF-74 suffers from properties that limit its usefulness as a lead, most notably it's extremely poor metabolic stability. To minimize unfavorable qualities, we investigated bioisosteric modification of the PF-74 scaffold as a first step in redeveloping this compound. Using a field-based bioisostere identification method, coupled with biochemical and biological assessment, we have created four new compounds that inhibit HIV-1 infection and that bind to the assembled CA hexamer. Detailed mechanism of action studies indicates that the modifications alter the manner in which these new compounds affect HIV-1 capsid core stability, as compared to the parental compound. Further investigations are underway to redevelop these compounds to optimize potency and drug-like characteristics and to deeply define the mechanism of action.

SUBMITTER: Xu JP

PROVIDER: S-EPMC6214487 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Exploring Modifications of an HIV-1 Capsid Inhibitor: Design, Synthesis, and Mechanism of Action.

Xu Jimmy P JP Francis Ashwanth C AC Meuser Megan E ME Mankowski Marie M Ptak Roger G RG Rashad Adel A AA Melikyan Gregory B GB Cocklin Simon S

Journal of drug design and research 20180813 2

Recent efforts by both academic and pharmaceutical researchers have focused on the HIV-1 capsid (CA) protein as a new therapeutic target. An interprotomer pocket within the hexamer configuration of the CA, which is also a binding site for key host dependency factors, is the target of the most widely studied CA inhibitor compound PF-3450074 (PF-74). Despite its popularity, PF-74 suffers from properties that limit its usefulness as a lead, most notably it's extremely poor metabolic stability. To m ...[more]

PMID: 30393786

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Project description:The HIV-1 CA protein has gained remarkable attention as a promising therapeutic target for the development of new antivirals, due to its pivotal roles in HIV-1 replication (structural and regulatory). Herein, we report the design and synthesis of three series of benzenesulfonamide-containing phenylalanine derivatives obtained by further structural modifications of PF-74 to aid in the discovery of more potent and drug-like HIV-1 CA inhibitors. Structure-activity relationship studies of these compounds led to the identification of new phenylalanine derivatives with a piperazinone moiety, represented by compound 11l, which exhibited anti-HIV-1NL4-3 activity 5.78-fold better than PF-74. Interestingly, 11l also showed anti-HIV-2ROD activity (EC50 = 31 nM), with almost 120 times increased potency over PF-74. However, due to the higher significance of HIV-1 as compared to HIV-2 for the human population, this manuscript focuses on the mechanism of action of our compounds in the context of HIV-1. SPR studies on representative compounds confirmed CA as the binding target. The action stage determination assay demonstrated that these inhibitors exhibited antiviral activities with a dual-stage inhibition profile. The early-stage inhibitory activity of compound 11l was 6.25 times more potent as compared to PF-74 but appeared to work via the accelerating capsid core assembly rather than stabilization. However, the mechanism by which they exert their antiviral activity in the late stage appears to be the same as PF-74 with less infectious HIV-1 virions produced in their presence, as judged p24 content studies. MD simulations provided the key rationale for the promising antiviral potency of 11l. Additionally, 11l exhibited a modest increase in HLM and human plasma metabolic stabilities as compared to PF-74, as well as a moderately improved pharmacokinetic profile, favorable oral bioavailability, and no acute toxicity. These studies provide insights and serve as a starting point for subsequent medicinal chemistry efforts in optimizing these promising HIV inhibitors.

Project description:The HIV p24 capsid protein has an essential, structural, and functional role in the viral replication cycle, being an interesting target for vaccine design, diagnostic tests, and new antiretroviral drugs (ARVs). The HIV-1 variability poses a challenge for the accuracy and efficiency of diagnostic and treatment tools. This study analyzes p24 diversity among HIV-1 variants and within its secondary structure in HIV-1 M, O, P, and N groups. All available HIV-1 p24 nucleotide sequences were downloaded from the Los Alamos HIV Sequence Database, selecting 23,671 sequences belonging to groups O, N, P, and M (9 subtypes, 7 sub-sub types, and 109 circulating recombinant forms or CRFs). Using a bioinformatics tool developed in our laboratory (EpiMolBio program), we analyzed the amino acid conservation compared to the HXB2 subtype B reference sequence and the V-markers, or amino acid changes that were specific for each variant with at least 10 available sequences. We inferred the p24 consensus sequence for HIV-1 and for each group to analyze the overall conservation in p24 main structural regions, reporting the percentage of substitutions per variant affecting the capsid assembly and molecule-binding, including those associated with resistance to the new capsid-inhibitor lenacapavir, and the key residues involved in lenacapavir-p24 interaction, according to the bibliography. Although the overall structure of p24 was highly conserved, the conservation in the secondary structure varied between HIV-1 variants and the type of secondary structure. All HIV-1 variants presented >80% amino acid conservation vs. HXB2 reference sequence, except for group M sub-subtype F1 (69.27%). Mutants affecting the capsid assembly or lenacapavir capsid-binding were found in <1% of the p24 consensus sequence. Our study reports the HIV-1 variants carrying 14 unique single V-markers in 9/38 group M variants and the level of p24 conservation in each secondary structure region among the 4 HIV-1 groups and group M variants, revealing no natural resistance to lenacapavir in any HIV-1 variant. We present a thorough analysis of p24 variability among all HIV-1 variants circulating to date. Since p24 genetic variability can impact the viral replication cycle and the efficacy of new p24-based diagnostic, therapeutic, and vaccine strategies, conservation studies must consider all HIV-1 variants circulating worldwide.

Dataset Information

Exploring Modifications of an HIV-1 Capsid Inhibitor: Design, Synthesis, and Mechanism of Action.

Publications

Exploring Modifications of an HIV-1 Capsid Inhibitor: Design, Synthesis, and Mechanism of Action.

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