Synthesis of inhibitors of HIV-Rev function

HIV-Rev功能抑制剂的合成

• 批准号: 6821925
• 负责人: Erik J. Sorensen
• 金额: $ 5.21万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6821925
• 关键词: antiviral agents; chemical binding; drug design /synthesis /production; human immunodeficiency virus; inhibitor /antagonist; transcription factor; virus protein; virus replication

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.

该研究项目是一项综合计划的一部分——针对 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。该研究部分的目标是合成化合物，筛选其抑制 Rev 与 RRE RNA 结合和 Rev 依赖性 mRNA 输出的能力。该提案描述了合成天然存在的 HIV Rev/RRE RNA 抑制剂 harziphilone 和 flephilone 类似物的策略，以及来自 Williamson 在项目 #1 中开发的虚拟库中具有 RNA 结合潜力的各种药物样分子。 harziphilone 和 flephilone 的 13C 标记变体的合成将有助于 NMR 研究，以阐明这些天然产物与病毒 mRNA 的 RRE 或 Rev-RRE 复合物形成的复合物的结构。这些研究产生的结构信息将指导 harziphilone 和 harziphilone 类似物的设计和合成 flephilone 旨在了解对效力​​和选择性至关重要的分子特征。此外，新颖和先例的多组分偶联反应将应用于合成具有药物样特性的多种小分子。这些化合物将由 Williamson 项目#1、Millar 项目#2 和 Gerace 项目#4 评估其作为 HIV Rev 功能抑制剂的效用。该项目将向多学科合作贡献一系列具有 RNA 结合和药物样特征的新型分子，探索破坏 HIV-1 Rev 蛋白和病毒 mRNA 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 用于开发针对艾滋病毒感染的新型抗病毒药物的化合物。