Synthesis of inhibitors of HIV-Rev function

该研究项目是一个全面计划的一部分-靶向HIV Rev的RNA结合和核输出-旨在表征HIV Rev功能并确定抑制HIV复制的新方法。本研究部分的目的是合成化合物，筛选其抑制Rev与RRE RNA结合和Rev依赖性mRNA输出的能力。该提案描述了用于合成天然存在的HIV Rev/RRE RNA抑制剂harziphilone和fleephilone的类似物以及来自威廉姆森在项目#1中开发的虚拟文库的具有RNA结合潜力的各种药物样分子的策略。合成13 C标记的harziphilone和fleephilone的变体将有助于NMR研究，以阐明这些天然产物与病毒mRNA的RRE或与Rev-RRE复合物形成的复合物的结构。由这些研究产生的结构信息将指导设计和合成哈茨菲隆的类似物， fleephilone在努力了解的分子特征的效力和选择性的关键。此外，新的和有先例的多组分偶联反应将被应用于具有药物样特征的多种小分子的合成。这些化合物将由威廉姆森项目1、Millar项目2和杰雷斯项目4评价其作为HIV Rev功能抑制剂的效用。该项目将为多学科合作提供一系列具有RNA结合和药物样特征的新型分子，这些分子将探索破坏HIV-1 Rev蛋白与病毒mRNA的RRE之间结合相互作用的治疗潜力。最终，这项研究可以提供新的线索， 用于开发针对HIV感染的新的抗病毒剂的化合物。

This research project is part of a comprehensive program-Targeting the RNA binding and nuclear export of HIV Rev-aimed at characterizing HIV Rev function and identifying new approaches for inhibiting the replication of HIV. The objective of this research component is to synthesize compounds that will be screened for their capacity to inhibit the binding of Rev to RRE RNA and Rev-dependent mRNA export. This proposal describes strategies for synthesizing analogues of the naturally occurring HIV Rev/RRE RNA inhibitors harziphilone and fleephilone as well as a wide variety of drug-like molecules with RNA-binding potential from a virtual library developed by Williamson in project #1. Syntheses of 13C-labeled variants of harziphilone and fleephilone will facilitate NMR studies to elucidate the structures of the complexes that these natural products make with the RRE of viral mRNA or with a Rev-RRE complex. The structural information yielded by these studies will guide the design and synthesis of analogues of harziphilone and fleephilone in an effort to understand the molecular features critical for potency and selectivity. In addition, both novel and precedented multi-component coupling reactions will be applied to syntheses of manifold small molecules that have drug-like characteristics. These compounds will be evaluated by Williamson project #1, Millar project #2, and Gerace project #4 for their utility as inhibitors of HIV Rev function. This project will contribute a collection of novel molecules possessing RNA-binding and drug-like features to a multi-disciplinary collaboration that will explore the therapeutic potential of disrupting the binding interaction between the HIV-1 Rev protein and the RRE of viral mRNA. Ultimately, this research could furnish new lead compounds for the development of new anti-viral agents against HIV-infection.