IRREVERSIBLE INHIBITORS OF HIV PROTEASE

HIV蛋白酶的不可逆抑制剂

• 批准号: 2068822
• 负责人: G. MARC LOUDON
• 金额: $ 14.06万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-11-01 至 1995-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2068822
• 关键词: AIDS; antiAIDS agent; aziridines; chemical models; computer graphics /printing; drug design /synthesis /production; endopeptidases; enzyme inhibitors; human immunodeficiency virus; virus protein

DESCRIPTION: (Adapted from Applicant's Abstract): The objective of the proposed research is the testing and development of a new concept for the design of inhibitors of HIV protease, an enzyme that has been demonstrated to be essential for the replication of HIV. A series of inhibitors are proposed, the structures of which incorporate elements that are known to induce binding to the protease, as well as a novel electrophilic aziridinyl moiety that will serve to react covalently with residues of the protease that appear to be conserved. The design of the inhibitors, the first phase of which has been completed as preliminary work, has employed molecular graphics, starting with the crystallographically-determined coordinates of a complex of the protease with a known noncovalent inhibitor. The structure of the noncovalent inhibitor serves as the starting point for the design of the covalent inhibitors, so that molecular graphics-based design represents a relatively small perturbation of a known structure. The synthesis and evaluation of the proposed inhibitors is described. The results of enzyme inhibition studies will be used to refine the molecular-graphics design of inhibitor structures. Chemical model systems are also proposed to test the use of aziridines as electrophilic enzyme-modifying reagents.

描述：（改编自申请人的摘要）： 拟议的研究是对新概念的测试和开发 HIV蛋白酶抑制剂的设计，一种酶 证明对于艾滋病毒的复制至关重要。 一系列 提出了抑制剂，其结构结合了元素 已知会诱导与蛋白酶的结合，以及一种新颖 亲电偶氮素基部分将与 蛋白酶的残留物似乎是保守的。 设计 抑制剂，其第一阶段已作为初步完成 工作，已经采用了分子图形，从 蛋白酶复合物的晶体学确定的坐标 具有已知的非共价抑制剂。 非共价的结构 抑制剂是共价设计的起点 抑制剂，因此基于分子图形的设计代表 已知结构的相对较小的扰动。 合成和 描述了所提出的抑制剂的评估。 结果 酶抑制研究将用于完善分子图 抑制剂结构的设计。还提出了化学模型系统 测试中氮嘧啶作为亲电酶修饰试剂的使用。