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.

该研究项目是针对艾滋病毒艾滋病毒艾滋病毒复兴功能的艾滋病毒艾滋病毒的RNA结合和核出口的全面计划的一部分，并确定了抑制艾滋病毒复制的新方法。该研究组成部分的目的是合成化合物，这些化合物将被筛选，以抑制REV与RRE RNA和REV依赖性mRNA导出的结合的能力。该提案描述了合成天然发生的HIV REV/RRE RNA抑制剂Harziphilone和Flepleephilone的策略，以及Williamson在项目＃1中的虚拟图书馆中具有RNA结合潜力的多种类似药物样的分子。 Harziphilone和Fleephilone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或Rev-RRE复合物的复合物结构。这些研究产生的结构信息将指导Harziphilone和 fleephilone努力了解效力和选择性至关重要的分子特征。此外，新型和先例的多组分耦合反应都将应用于具有类似药物的特征的歧管小分子的合成。这些化合物将由Williamson Project＃1，Millar Project＃2和Gerace Project＃4评估，以作为HIV Rev功能抑制剂的实用性。该项目将贡献一系列具有RNA结合和类似药物的新分子的集合，以探索破坏HIV-1 REV蛋白与病毒mRNA RRE之间的结合相互作用的治疗潜力。最终，这项研究可以提供新的领导 用于开发新的抗病毒药物的化合物。