SYNTHESIS OF CRUZAIN INHIBITORS

CruzAIN抑制剂的合成

• 批准号: 6268162
• 负责人: WILLIAM R ROUSH
• 金额: $ 13.29万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 1999-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6268162
• 关键词: Trypanosoma cruzi; active sites; antiprotozoal agents; chemical kinetics; crystallization; cysteine endopeptidases; drug design /synthesis /production; enzyme activity; organometallic compounds; peptide analog; protease inhibitor; protein structure function; site directed mutagenesis

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.

该计划的具体目标是设计和综合改进的 主要半胱氨酸蛋白酶 cruzain 的活性位点定向抑制剂 克氏锥虫。 肽模拟物和非肽抑制剂将 借助以下见解进行设计： (i) Fletrick 和 McGrath 最近解决的 X 射线结构， 其活性位点有一个共价结合的 Z-Phe-Ala-FMK 抑制剂： (ii) 了解二肽的结构要求 McKerrow 和同事已经证明了氟甲基酮 (FMK) 是纯化 cruzain 的有效、不可逆抑制剂，并且 在体内具有抗克氏锥虫活性；和， (iii) 来自 DOCK 生成的、非 肽先导抑制剂结构源自 Cohen 和 戒指。 此外，一类基于E-的新型半胱氨酸蛋白酶抑制剂 将开发64个主题。 具体地，抑制剂并入 将合成环氧丙酰酮（EPK）子结构并 由我们的寄生虫学和生物化学合作者 McKerrow 进行评估 和恩格尔，在加州大学旧金山分校。 进一步修改和优化 如果有希望的活性，将进行最初的 EPK 抑制剂 观察到 cruzain 抑制剂。 这些努力的重点是确定先导化合物的修饰 抑制剂结构已确定（参见背景和意义 节），以增强它们在体内的使用。 吸收等因素 通过口服途径，消除可能有助于 毒副反应，并增强活性和特异性 将评估针对目标蛋白酶 cruzain 的抑制剂 在涉及我们综合小组的迭代循环中，计算机建模 组（Cohen）、蛋白质结构组（McGrath、Fletterick 和 Craik），以及该程序的寄生虫学和生物化学组成部分 （麦克罗和恩格尔）。 这些共同努力将导致设计和 合成更加特异和有效的 cruzain 抑制剂。