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：
10190832
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 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10190832
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.

项目摘要 HIV宿主限制因子APOBEC3G（A3G）可以通过诱导的灾难性抑制HIV 病毒基因组中的突变。 HIV VIF蛋白通过与A3G结合并指导来保护HIV 它是蛋白酶体降解途径。提议的SBIR I期的意义研究是，VIF仍然是一个新的抗病毒靶标的，其临床潜力尚未完全探索。尽管对VIF进行了大量的学术研究，但只有有限的努力用于确定 VIF的小分子拮抗剂。 Oyagen，Inc。是当前追求的唯一商业实体以有意义的方式与VIF特别相互作用的化学支架的识别药物开发。先前抗VIF药物发现工作的继承限制是使用在“命中”可能是由于多种作用机理引起的原始药物筛查中。我们设计了一个活细胞淬灭的粮食（FQRET）报告基因测定法，该测定法可以选择膜 - 使用VIF突变体的VIF和A3G之间蛋白质 - 蛋白质相互作用的渗透性拮抗剂保留与A3G结合的野生类型 A3G降解。从一个110k小分子的类似药物的化合物的屏幕中确定的165优先考虑他的进一步分析。尽管一些化合物依赖于剂量 A3G（一种化合物）的VIF结合的拮抗剂，以下称为C5，是无毒性的并显示剂量依赖性：i）抑制VIF依赖性A3G降解，ii）抑制假型HIV复制和iii）促进了A3G在病毒中的增加。这里我们提出了一种创新的药物发现关键路径，以优化新型的抗HIV铅化合物从C5预期II期SBIR药代动力学分析，体内效率测试和辅助研究。 I阶段SBIR目标将重点放在结构活动关系（SAR）上 C5脚手架的药物化学，用于抗HIV化合物的命中至铅的优化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免受依赖VIF的降解。