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Development of Lead Inhibitors of HIV Vif Binding to Antiretroviral A3G Through Medicinal Chemistry

通过药物化学开发 HIV Vif 与抗逆转录病毒 A3G 结合的先导抑制剂

基本信息

批准号：
10079868
负责人：
Jason Douglas Salter
金额：
$ 28.64万
依托单位：
OYAGEN, INC.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10079868
关键词：
APOCEC3G gene Address Affect Agonist Anti-HIV Agents Anti-Retroviral Agents Antiviral Agents Binding Biological Assay Cell Membrane Permeability Cells Chemicals Clinical Complementary DNA Complex Critical Pathways Custom Degradation Pathway Development Dose Drug Kinetics Drug Screening Drug Targeting Fluorescence Resonance Energy Transfer Genomics HIV HIV Budding HIV Genome HIV Protease HIV-1 Host Defense In Vitro Infection Integrase Lead Mediating Molecular Probes Mutagenesis Mutation Peripheral Blood Mononuclear Cell Pharmaceutical Chemistry Pharmaceutical Preparations Phase Polyubiquitination Positioning Attribute Property Proteins Recovery Reporter Reporting Research Reverse Transcription Selection Criteria Signal Transduction Small Business Innovation Research Grant Source Structure-Activity Relationship Testing Therapeutic Validation Viral Viral Genome Viral Proteins Virion Virus Inhibitors Virus Replication analog anti-viral efficacy base cytotoxicity design drug candidate drug development drug discovery efficacy testing elongin C high throughput screening in vivo indexing inhibitor/antagonist innovation lead optimization multicatalytic endopeptidase complex mutant novel particle pharmacophore phase 1 study phase 2 study pre-clinical preclinical development prevent protein protein interaction receptor recruit scaffold screening small molecule small molecule libraries ubiquitin-protein ligase

项目摘要

Project Summary The HIV host restriction factor APOBEC3G (A3G) can inhibit HIV by inducing catastrophic mutations in the viral genome. The HIV Vif protein protects HIV by binding to A3G and directing it to the proteasomal degradation pathway. The significance of the proposed SBIR phase I research is that Vif remains a new antiviral target whose clinical potential has yet to be fully explored. Despite much academic research on Vif, only a limited effort has gone toward identifying small molecule antagonists of Vif. OyaGen, Inc. is the only commercial entity currently pursuing the identification of chemical scaffolds that specifically interact with Vif in meaningful ways for drug development. An inherent limitation of prior anti-Vif drug discovery efforts has been the use of primary drug screens in which ‘hits’ may be due to more than one mechanisms of action. We designed a live cell quenched FRET (FqRET) reporter assay that enables selection of membrane- permeable antagonists of protein-protein interactions between Vif and A3G using a Vif mutant that retains wild type binding to A3G but no longer binds to Elongin C and no longer facilitates A3G degradation. From a screen of a 110K small molecule library of drug-like compounds we identified 165 prioritized his for further analysis. Although a few compounds were dose-dependent antagonists of Vif binding of A3G, one compound, hereafter referred to as C5, was non-cytotoxic and displayed dose-dependent: i) inhibition of Vif-dependent A3G degradation, ii) inhibition of pseudotyped HIV replication and iii) promoted an increased incorporation of A3G in virions. Here we propose an innovative drug discovery critical path to optimize a novel anti-HIV lead compound from C5 in anticipation of phase II SBIR pharmacokinetic analysis, in vivo efficacy testing, and IND-enabling studies. The Phase I SBIR Aims will focus on structure-activity relationship (SAR) medicinal chemistry of the C5 scaffold for hit-to-lead optimization of anti-HIV compound whose antiviral activity is mechanistically due to its function as a Vif antagonist that protects A3G from Vif-dependent degradation.

项目总结