DIMERIZATION INHIBITORS OF HIV-1 PROTEASE AND INTEGRASE

HIV-1 蛋白酶和整合酶的二聚化抑制剂

• 批准号: 6413424
• 负责人: JEAN A CHMIELEWSKI
• 金额: $ 1.84万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-01 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6413424
• 关键词: X ray crystallography; alanine; antiAIDS agent; calorimetry; crosslink; crystallization; dimer; drug design /synthesis /production; enzyme inhibitors; enzyme structure; human immunodeficiency virus 1; integrase; monomer; nuclear magnetic resonance spectroscopy; protease inhibitor; protein protein interaction; thermodynamics; tissue /cell culture; virus protein

Disrupting protein-protein interactions in multi-subunit enzymes is currently an underutilizes mode of inhibition. This proposal seeks to answer fundamental questions concerning the chemistry and biology of disrupting protein-protein interactions, and utilizes dimeric HIV protease and integrase as templates to address the questions. Specific Questions to be Addressed Protease Inhibition Based on our current model of binding, can we identify modifications that will increase inhibitor affinity for an HIV protease monomer? How potent an inhibitor is needed to shift the dimerization equilibrium of HIV protease and effectively reduce HIV maturation? What are the structural and thermodynamic effects of inhibvitor5 modifications on the protease monomer/inhibitor complex? Integrase Inhibition How general is the approach developed for dimerization inhibition of HIV protease, can it be applied to the inhibition of a structurally different protein such as HIV integrase?

目前，破坏多亚基酶中蛋白质-蛋白质相互作用是一种未充分利用的抑制模式。该提案旨在回答有关破坏蛋白质-蛋白质相互作用的化学和生物学的基本问题，并利用二聚体 HIV 蛋白酶和整合酶作为模板来解决这些问题。需要解决的具体问题 蛋白酶抑制 根据我们目前的结合模型，我们能否确定能够增加抑制剂对 HIV 蛋白酶单体亲和力的修饰？ 需要多强的抑制剂才能改变 HIV 蛋白酶的二聚平衡并有效降低 HIV 成熟？ inhibvitor5 修饰对蛋白酶单体/抑制剂复合物的结构和热力学影响是什么？整合酶抑制 用于 HIV 蛋白酶二聚化抑制的方法有多普遍，是否可以应用于结构不同的蛋白质（例如 HIV 整合酶）的抑制？