TOWARD PEPTIDEMIMETIC INHIBITORS OF ASPARTIC PROTEASES

天冬氨酸蛋白酶的拟肽抑制剂

• 批准号: 2690070
• 负责人: DANIEL H RICH
• 金额: $ 30.64万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 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 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2690070
• 关键词: X ray crystallography; active sites; aspartic endopeptidases; chemical models; drug design /synthesis /production; pepsin; peptide analog; protease inhibitor; protein binding

The goal of this research is to develop new methods for the design and synthesis of Type-III Peptidomimetic inhibitors of aspartic proteases. A Type-III mimetic, is an organic structure, distinctly different in shape and atom type from a peptide substrate, that binds so as to complement the local topography in the enzyme active site. These are considered likely to lead efficiently to orally bioavailable enzyme inhibitors. Model studies with pepsin and R. Chinensis pepsin will be continued by creating potential candidates for synthesis by applying the structure-generating program, GrowMol, to two different classes of enzyme-inhibitor complexes: (1) those formed from tight-binding transition-state analogs bound to the target enzyme; and (2) those formed from weaker binding inhibitors bound to a destabilized enzyme. Of the many potential synthetic targets generated, Beilstein's CrossFire is used to identify synthetically accessible templates or core structures from which to build the peptidomimetic. These are further refined by the chemist, synthesized, assayed against the target enzyme and when active, their binding mode to the enzyme will be determined by X-ray crystrallography. New strategies for the Design of Protease Inhibitors will result and the goal is to find ways to design Type-III peptidomimetic inhibitors directly from the structures of peptide inhibitors bound to the target enzyme. These strategies will be applied to two clinically important aspartic proteases, HIV protease and plasmepsin II.

这项研究的目的是为设计和 天冬氨酸蛋白酶的III型肽抑制剂的合成。 III型模拟物，是一个有机结构，在 从肽底物的形状和原子类型，与 补充酶活性位点中的局部地形。 这些都是 被认为可能有效地导致口服生物利用酶 抑制剂。 胃蛋白酶和Chinensis胃蛋白酶的模型研究将是 通过应用 结构生成程序，growmol，两个不同类别的类别 酶抑制剂复合物：（1）由紧密结合形成的酶 与目标酶结合的过渡状态类似物； （2）那些 由结合较弱的结合抑制剂形成，与不稳定的酶结合。 在产生的许多潜在合成目标中，贝尔斯坦的交火 用于识别合成访问的模板或核心 从中构建肽的结构。 这些是进一步的 由化学家精炼，合成，针对目标酶进行测定 当活跃时，它们与酶的结合模式将由 X射线碎屑。 蛋白酶设计的新策略 抑制剂将导致，目标是找到设计类型III的方法 直接来自肽结构的肽型抑制剂 与靶酶结合的抑制剂。这些策略将应用 到两个临床上重要的天冬氨酸，HIV蛋白酶和 质子蛋白II。