克氏锥虫鲨烯合成酶tcSQS催化反应机理的研究及基于复合物结构的抑制剂设计

项目名称： 克氏锥虫鲨烯合成酶tcSQS催化反应机理的研究及基于复合物结构的抑制剂设计

项目编号： No.31300615

项目类型： 青年科学基金项目

立项/批准年度： 2014

项目学科： 生物科学

项目作者： 黄骏翔

作者单位： 中国科学院天津工业生物技术研究所

项目金额： 22万元

中文摘要： 美洲锥虫病是由克氏锥虫引起的一种寄生虫病，广泛流行于中南美洲，造成了数千万人的感染和巨大的经济损失，市场上仅有的两种化学药物毒性巨大、抗药性明显，开发新的抗寄生虫药物迫在眉睫。由于克氏锥虫对内源的麦角固醇有严格的需求，开发麦角固醇合成途径中鲨烯合成酶SQS的特异性抑制剂是治疗美洲锥虫病的有效手段。但目前对SQS的催化反应机理缺乏了解，锥虫SQS特异性抑制剂的结构特征也尚不明确。本课题拟利用X光晶体学的方法，解析克氏锥虫鲨烯合成酶tcSQS分别与底物或类似物FSPP、NADPH、反应中间体PSPP的复合物结构，解释SQS催化反应的机理；同时，解析tcSQS和人源鲨烯合成酶hSQS分别与高活性和高选择性的奎宁类抑制剂的复合物结构，通过分析影响抑制剂活性和选择性的结构特征，设计高活性和高选择性的抑制剂。

中文关键词： 美洲锥虫病；克氏锥虫；角鲨烯合成酶；结构；抑制剂

英文摘要： American trypanosomiasis is a parasitic disease caused by Trypanosoma cruzi and widely spread in South American countries. More than 10 million people have been infected, which cost the American economy $900 million a year. Currently the only two available chemotherapeutic agents have frequent toxic side effects and rising drug resistance. Developing novel anti-trypanosomiasis agents has drawn enormous attention. Trypanosoma cruzi have a strict requirement for specific endogenous ergosterol for survival and growth. Squalene synthase (SQS) catalyzes the first committed step in sterol biosynthesis and is a promising target for anti-parasitic chemotherapy. Now neither the SQS reaction mechanism nor the structure characterizations of selective inhibitors is fully understood. In this study, we plan to resolve the crystal structures of tcSQS in apo-form and in complex with three ligands, FSPP, NADPH and PSPP, to explain the mechanism of SQS reaction. We also plan to resolve the crystal structures of tcSQS and hSQS in complex with the potency inhibitors and selective inhibitors, respectively. These complex structures can provide the information of the inhibitor structures and can guide designing the high potency selective inhibitors. This study will elucidate the molecular mechanism of SQS reaction and help design high

英文关键词： American trypanosomiasis；Trypanosoma cruzi；squalene synthase；structrues；inhibitors