DESIGN, SYNTHESIS AND CHARACTERIZATION OF FLUORINATED HIV PROTEASE INHIBITOR

氟化 HIV 蛋白酶抑制剂的设计、合成和表征

• 批准号: 6290021
• 负责人: Robert E London
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6290021
• 关键词: AIDS; HIV envelope protein gp120; HIV infections; active sites; antiAIDS agent; antiviral agents; aspirin; drug design /synthesis /production; drug screening /evaluation; enzyme activity; intermolecular interaction; nuclear magnetic resonance spectroscopy; pepsin; pharmacokinetics; phenylalanine analog; protease inhibitor; purine nucleoside phosphorylase; virus protein

HIV protease is an important chemotherapeutic target for the treatment of AIDS; the most successful treatments developed to date involve combinations of protease inhibitors with nucleoside analogs which inhibit the reverse transcriptase. However, the high mutation rate of the virus makes it possible to select against most of the protease inhibitors which thus far have been developed. Recent work on this project has included several goals: 1. Development of HIV protease mutants with greater stability, particularly to allow NMR studies of the uncomplexed enzyme; 2. Evaluation of a new inhibition strategy based on the use of inhibitors with multiple binding modes; 3. Development of a new NMR approach for inhibitor design. The latter method, called the inter-ligand Overhauser effect, allows the investigation of structural relationships between weakly bound ligands so that they can be combined to yield a single, more potent inhibitor. - HIV protease; proline; NMR; nuclear Overhauser effect; inhibitor binding

HIV蛋白酶是治疗AIDS的重要化疗靶点;迄今为止开发的最成功的治疗方法涉及蛋白酶抑制剂与抑制逆转录酶的核苷类似物的组合。然而，该病毒的高突变率使得有可能针对迄今为止已经开发的大多数蛋白酶抑制剂进行选择。该项目最近的工作包括几个目标：1。开发具有更大稳定性的HIV蛋白酶突变体，特别是允许对未复合的酶进行NMR研究; 2.评价基于使用具有多种结合模式的抑制剂的新抑制策略; 3.一种新的NMR缓蚀剂设计方法的开发。后一种方法，称为配体间Overhauser效应，允许研究弱结合配体之间的结构关系，以便它们可以结合在一起，产生一个单一的，更有效的抑制剂。- HIV蛋白酶;脯氨酸;核磁共振;核Overhauser效应;抑制剂结合