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.

项目概要 HIV宿主限制因子APOBEC3G (A3G)可以通过诱导灾难性的感染来抑制HIV HIV Vif 蛋白通过与 A3G 结合并指导来保护 HIV。它对蛋白酶体降解途径的重要性。研究表明，Vif 仍然是一个新的抗病毒靶点，其临床潜力尚未充分发挥尽管对 Vif 进行了大量的学术研究，但在识别方面所做的努力却很有限。 OyaGen, Inc. 是目前唯一追求小分子拮抗剂的商业实体。鉴定以有意义的方式与 Vif 特异性相互作用的化学支架先前的抗 Vif 药物发现工作的一个固有限制是使用。初级药物筛选中的“命中”可能是由于不止一种作用机制造成的。设计了一种活细胞猝灭 FRET (FqRET) 报告基因测定法，可以选择膜- 使用 Vif 突变体对 Vif 和 A3G 之间的蛋白质-蛋白质相互作用进行渗透性拮抗剂保留野生型与 A3G 的结合，但不再与 Elongin C 结合，并且不再促进 A3G 降解。通过对 110K 类药物化合物小分子库的筛选，我们确定 165 优先进行进一步分析，尽管其中一些化合物具有剂量依赖性。 Vif 与 A3G 结合的拮抗剂，一种化合物，以下称为 C5，是非细胞毒性的并表现出剂量依赖性：i) 抑制 Vif 依赖性 A3G 降解，ii) 抑制假型 HIV 复制和 iii) 促进 A3G 在病毒粒子中的掺入增加。我们提出了创新药物发现的关键路径来优化新型抗 HIV 先导化合物来自 C5 的预期 II 期 SBIR 药代动力学分析、体内功效测试以及第一阶段 SBIR 目标将侧重于结构-活性关系 (SAR)。 C5支架的药物化学，用于抗HIV化合物的命中到先导优化，其抗病毒活性在机械上是由于其作为 Vif 拮抗剂的功能，可保护 A3G 免受 Vif 依赖性降解。