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蛋白酶是治疗艾滋病的重要化学治疗靶标。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。但是，病毒的高突变率使得可以选择迄今为止已经开发的大多数蛋白酶抑制剂。该项目的最新工作包括几个目标：1。稳定性更高的HIV蛋白酶突变体的发展，尤其是允许对未复杂酶进行NMR研究； 2。基于使用具有多种结合模式的抑制剂的新抑制策略的评估； 3。开发一种新的NMR抑制剂设计方法。后一种方法称为配体间高刺效应，允许研究弱结合的配体之间的结构关系，以便可以将它们组合起来产生一个更有效的抑制剂。 - 艾滋病毒蛋白酶；脯氨酸NMR;核透射效应；抑制剂结合