SYNTHESIS OF INHIBITORS OF PARASITIC CYSTEINE PROTEASES

寄生半胱氨酸蛋白酶抑制剂的合成

• 批准号: 6338609
• 负责人: WILLIAM R ROUSH
• 金额: $ 11.17万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-01 至 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6338609
• 关键词: Leishmania; Plasmodium falciparum; Trypanosoma cruzi; antiprotozoal agents; cysteine endopeptidases; drug design /synthesis /production; peptide analog; peptide chemical synthesis; protease inhibitor; protein structure function

The specific aim of this program is to design and synthesize improved active site directed inhibitors of cruzain, the major cysteine protease of Trypanosoma cruzi. Peptide mimetics and non-peptidic inhibitors will be designed with the aid of insights deriving from: (i) The X-ray structure recently solved by Fletterick and McGrath, which has a covalently bound Z-Phe-Ala-FMK inhibitor at the active site: (ii) Knowledge of the structural requirements of the dipeptide fluoromethyl ketones (FMK) that McKerrow and coworkers have demonstrated to be potent, irreversible inhibitors of purified cruzain, and also to be active in vivo against Trypanosoma cruzi; and, (iii) Structural information deriving from the DOCK-generated, non- peptidic lead inhibitor structures deriving from the work of Cohen and Ring. In addition, a new class of cysteine protease inhibitors based on the E- 64 motif will be developed. Specifically, inhibitors incorporating epoxypropionyl ketone (EPK) substructures will be synthesized and evaluated by our parasitology and biochemistry collaborators, McKerrow and Engel, at UC San Francisco. Further modifications and optimization of the initial EPK inhibitors will be performed if promising activity as cruzain inhibitors is observed. The focus of these efforts is to identify modifications of the lead inhibitor structures already identified (see Background and Significance Section) so as to enhance their use in vivo. Factors such as absorption from the oral route, eliminating functional groups that may contribute to toxic side reactions, and enhancing the activity and specificity of the inhibitors against the targeted protease, cruzain, will be evaluated in iterative cycles involving our synthesis group, the computer modeling group (Cohen), the protein structure groups (McGrath, Fletterick and Craik), and the parasitology and biochemistry components of this program (McKerrow and Engel). These combined efforts will lead to the design and synthesis of ever more specific and potent cruzain inhibitors.

该计划的具体目的是设计和合成改进 主动部位指示Cruzain的抑制剂，Cruzain，主要半胱氨酸蛋白酶 克鲁齐锥虫。 肽模拟物和非肽抑制剂将 借助洞察力来设计： （i）Fletterick和McGrath最近解决的X射线结构， 在活性部位具有共价结合的Z-Phe-Ala-FMK抑制剂： （ii）了解二肽的结构要求 McKerrow和同事证明的氟甲基酮（FMK） 为了有效，不可逆的纯化Cruzain抑制剂，也 在体内活跃对抗锥虫克鲁兹；和， （iii）从码头生成的，非 - 肽铅抑制剂结构，源自科恩的工作 戒指。 另外，基于E-的新类半胱氨酸蛋白酶抑制剂 将开发64个图案。 具体而言，抑制剂合并 环氧丙烷基酮（EPK）子结构将合成，并 由我们的寄生学和生物化学合作者McKerrow评估 和恩格尔（Engel）在加州大学旧金山分校。 进一步的修改和优化 如果有希望的活动为 观察到克鲁济氏蛋白抑制剂。 这些努力的重点是确定铅的修改 抑制剂结构已经确定（请参阅背景和意义 部分）以增强其在体内的使用。 吸收等因素 从口头途径中，消除可能贡献的官能团 对有毒的侧面反应，并增强 将评估针对目标蛋白酶Cruzain的抑制剂 在涉及我们的合成组的迭代周期中，计算机建模 组（Cohen），蛋白质结构组（McGrath，Fletterick和 Craik），以及该计划的寄生学和生物化学组成部分 （McKerrow和Engel）。 这些合并的努力将导致设计和 综合越来越具体和有效的cruzain抑制剂。