Preclinical Development of HIV-1 Vif Antagonists

描述（由申请人提供）：本项目申请的目的是开发靶向中枢神经系统和外周HIV-1复制库的新型治疗药物。在U19的支持下，我们已经确定了靶向vif-apobec轴并特异性抑制vif依赖性病毒复制的新型小分子。构效关系（SAR）研究已经鉴定出在原代巨噬细胞中具有活性的有效类似物（IC 50 <100 nm），显示CNS生物利用度并表现出独特的抗性特征。我们建议在这些发现的基础上优化这些小分子vif拮抗剂的活性和特异性，并根据抗病毒效力/特异性、Pk/Tox和抗性谱，优先考虑最有希望的类似物，用于在SIV/猕猴脑炎模型中分析功效。构成本计划项目申请的各个项目和核心及其作用如下： 项目1。Tariq Rana博士，Sanford-Burnham研究所，Vif拮抗作用：铅发现和SAR。 项目2.马里奥史蒂文森，博士，迈阿密大学医学院。Vif拮抗作用：SAR的病毒学支持和抑制剂耐药的分子机制。 项目3。苏珊·威斯特摩兰，医学博士，新英格兰灵长类研究中心。Vif拮抗作用：在SIV诱导的脑炎猕猴模型中的疗效评价。 核心A，行政。马里奥史蒂文森，迈阿密大学医学院。协调各个组成部分的活动以及与外部科学咨询委员会的互动。 核心B。Agneta von Gegerfelt博士Bioqual Inc. SIV病毒载量测定和小动物Pk/Tox研究。Bioqual，Inc.将作为这个项目申请的非学术核心。在该计划项目中进行的研究将推进临床候选药物的开发，并为vif拮抗剂作为治疗HIV-1感染的新药的临床评价奠定基础。

DESCRIPTION (provided by applicant): The objective of this program project application is to develop novel therapeutics that target CNS and peripheral reservoirs of HIV-1 replication. Under the auspices of a U19, we have identified novel small molecules that target the vif-apobec axis and that specifically inhibit vif-dependent viral replication. Structure Activity Relationship (SAR studies have identified potent analogs (IC50 <100nm) that are active in primary' macrophage, show CNS bioavailability and exhibit unique resistance profiles. We propose to build on these discoveries to optimize the activity and specificity of these small molecule vif antagonists and, on the basis of antiviral potency/specificity, Pk/Tox and resistance profiles, prioritize the most promising analogs for analysis efficacy in a SlV/macaque model of encephalitis. The individual projects and cores that constitute this program project application and their roles are as follows: Project 1. Tariq Rana, Ph.D., Sanford-Burnham Institute, Vif antagonism: lead discovery and SAR. Project 2. Mario Stevenson, Ph.D., University of Miami Medical School. Vif antagonism: Virologic support for SAR and molecular mechanisms of inhibitor resistance. Project 3. Susan Westmoreland, VMD, New England Primate Research Center. Vif antagonism: evaluation of efficacy in a macaque model of SIV-induced encephalitis. Core A, Administration. Mario Stevenson, University of Miami Medical School. Coordination of the activities of the individual components and interaction with the external Scientific Advisory Board. Core B. Agneta von Gegerfelt' Ph.D., Bioqual Inc. SIV viral load assays and small animal Pk/Tox studies. Bioqual, Inc. will serve as a non-academic core on this program project application. Studies undertaken in this program project will advance the development of a clinical candidate and set the stage for the clinical evaluation of vif antagonists as new agents for the treatment of HIV-1 infection.