IRREVERSIBLE HIV-1 PROTEASE INHIBITORS--DESIGN/SYNTHESIS

不可逆 HIV-1 蛋白酶抑制剂——设计/合成

• 批准号: 2188524
• 负责人: RALPH F HIRSCHMANN
• 金额: $ 11.81万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-01-01 至 1996-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2188524
• 关键词: antiAIDS agent; drug design /synthesis /production; endopeptidases; enzyme inhibitors; human immunodeficiency virus 1; virus protein

DESCRIPTION: (Adapted from Applicant's Abstract). The prinicipal aim of this research program is to explore a new approach to the design and synthesis of irreversible enzyme inhibitors. Initially the investigators plan to apply this new concept to irreversible inhibitors of HIV-1 protease. The central thesis of this program is the strategic attachment of an a-dicarbonyl unit to a potent reversible enzyme inhibitor such that it becomes an irresversible inhibitor. To achieve these design objectives the applicant plans to (1) identify an enzyme which has been shown by X-ray crystallography or other means to possess an arginine residue near the active site; (2) select an appropriate known, high affinity inhibitor of that enzyme; and then (3) attach a dicarbonyl containing substituent to the inhibitor in such a way as to allow the arginine side chain and dicarbonyl unit to approach within bonding distance without interfering with the recognition of the inhibitor by the enzyme.

描述：（改编自申请人的摘要）。 主要目的 该研究计划是探索一种新的设计方法， 不可逆酶抑制剂的合成。 最初 调查人员计划将此新概念应用于不可逆的抑制剂 HIV-1蛋白酶。 该计划的中心论点是战略 A-DiCarbonyl单元附着在有效的可逆酶上 抑制剂使其成为一种不可逆转的抑制剂。 实现 这些设计目标申请人计划（1）识别酶 X射线晶体学或其他具有 活跃部位附近的精氨酸残留物； （2）选择适当的 已知的，该酶的高亲和力抑制剂；然后（3）附加 含有抑制剂取代基的dicarbonyl的方式 允许精氨酸侧链和双骨单元在内部接近 粘结距离而不会干扰识别 通过酶抑制剂。