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.

这项研究项目是一个综合性项目的一部分--以HIV Rev的RNA结合和核输出为目标--旨在表征HIV Rev的功能，并确定抑制HIV复制的新方法。这项研究的目的是合成化合物，以筛选其抑制REV与RRE RNA结合和REV依赖的mRNA输出的能力。这项建议描述了从威廉姆森在项目1中开发的虚拟文库中合成天然存在的HIV Rev/RRE RNA抑制剂HarziPhilone和FleePhilone的类似物以及各种具有RNA结合潜力的类药物分子的策略。13C标记的HarziPhilone和FleePhilone变体的合成将有助于核磁共振研究，以阐明这些天然产物与病毒mRNA的RRE或与REV-RRE复合体的结构。这些研究获得的结构信息将指导哈齐普隆和哈齐普隆类似物的设计和合成。 努力了解对效力和选择性至关重要的分子特征。此外，新颖的和先例的多组分偶联反应都将应用于合成多种具有类药物特性的小分子。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。该项目将为多学科合作贡献一系列具有RNA结合和药物样特征的新分子，以探索破坏HIV-1Rev蛋白和病毒mRNA的RRE之间的结合作用的治疗潜力。最终，这项研究可能会提供新的线索 用于开发抗艾滋病毒感染的新型抗病毒药物的化合物。