DESIGN AND ORGANIC SYNTHESIS OF INHIBITORS OF FIV PROTEASE

FIV蛋白酶抑制剂的设计与有机合成

• 批准号: 6340973
• 负责人: CHI-HUEY WONG
• 金额: $ 11.38万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6340973
• 关键词: X ray crystallography; active sites; antiviral agents; artificial intelligence; aspartate; aspartic endopeptidases; chemical kinetics; chemical models; chemical structure function; chemical synthesis; drug design /synthesis /production; enzyme mechanism; enzyme substrate complex; feline immunodeficiency virus; human immunodeficiency virus 1; model design /development; nonradiation isotope effect; nuclear magnetic resonance spectroscopy; protease inhibitor; protein structure; stereochemistry; virus protein

This research will develop rational approaches to the design and synthesis of inhibitors of the aspartyl protease from the feline immunodeficiency virus (FIV) and from the human immunodeficiency virus (HIV-1). It will focus on the following programs: 1. Develop effective and high-affinity small peptide substrates containing a scissle Tyr-Pro bond based on the sequences around the cleavage sites of FIV protease. 2. Investigate the mechanism of FIV protease reaction with synthetic substrates. 3. Design and synthesize Tyr-Pro peptide isostere and transition state analog inhibitors, or mechanism-based inactivators based on its cleavage reaction catalyzed by FIV and HIV protease. 4. Use computer-assisted and mechanism-based rational drug design cycles to improve the potency of inhibitors; incorporate additional peptide or nonpeptide complementarity components to the inhibitors. 5. Develop new chemistry for the synthesis of protease inhibitors in general and aspartyl proteases in particular. Significant contributions in the areas of biomedicine, drug design, and synthetic organic chemistry are expected. These developments will facilitate the discovery and development of new therapeutic agents for AIDS.

这项研究将开发出设计和综合的合理方法 从猫免疫缺陷中的天冬氨酸蛋白酶的抑制剂的抑制剂 病毒（FIV）和人类免疫缺陷病毒（HIV-1）。 会 专注于以下程序： 1。发展有效和高亲和力小肽底物 基于周围的序列包含剪刀Tyr-Pro键 FIV蛋白酶的切割位点。 2。研究与合成的FIV蛋白酶反应的机制 基材。 3。设计和合成Tyr-Pro肽ISOSTOSTEE和过渡状态 基于模拟抑制剂或基于机制的灭活剂 FIV和HIV蛋白酶催化的切割反应。 4。使用基于计算机和机制的理性药物设计周期 提高抑制剂的效力；掺入其他肽 或抑制剂的非肽互补成分。 5。开发新的化学方法，用于合成蛋白酶抑制剂 尤其是一般和天冬氨酸蛋白酶。 生物医学，药物设计和 预计合成有机化学。 这些事态发展会 促进新的治疗剂的发现和开发 艾滋病。