热休克蛋白47（HSP47）抑制剂的发现、优化及其在抗纤维化疾病中的作用研究

项目名称： 热休克蛋白47（HSP47）抑制剂的发现、优化及其在抗纤维化疾病中的作用研究

项目编号： No.81502981

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 蔡海燕

作者单位： 上海交通大学

项目金额： 17.9万元

中文摘要： 胶原是人体内含量最多的蛋白质，对维护组织器官结构的完整性至关重要。胶原蛋白合成的异常会导致组织纤维化等多种疾病。热休克蛋白47（HSP47）是丝氨酸蛋白酶抑制剂（Serpin）家族的一员，是胶原合成过程中不可或缺的特异性分子伴侣。现有研究发现HSP47在纤维化病灶中表达显著增加，且特异性地抑制HSP47的功能有助于纤维化疾病的治疗。本申请人在前期的研究中，通过计算机辅助药物设计等手段发现了两个可以有效抑制HSP47与胶原结合的小分子抑制剂。在此基础上，本项目拟通过子结构搜索等基于结构的药物设计方法对其进行进一步结构优化。同时我们将建立新的高通量生物活性筛选平台，更大范围地筛选HSP47小分子抑制剂，并通过细胞模型评价这些化合物的抗纤维化活性。这项研究结果将为设计新型的抗纤维化疾病药物奠定基础。

中文关键词： HSP47抑制剂；抗纤维化；胶原；药物设计；结合机制

英文摘要： Collagen, the most abundant mammalian protein, is critical to form specialized networks that bind cells together. The abnormal biosynthesis of collagen will cause various diseases such as tissue fibrosis. Heat shock protein 47 (HSP47), a member of serine protease inhibitor (Serpin) family, is a single-substrate molecular chaperone crucial for collagen biosynthesis. The expression of HSP47 is significantly increased in the progression of various fibrotic lesions. Inhibition of HSP47 might be a novel therapeutic target for the treatment of fibrotic diseases. In our previous study, we discovered two small molecular HSP47 inhibitors, which can effectively inhibit the interactions between HSP47 and collagen, using the approach of computer-aided drug design. Based on the active molecular structures, we will carry out structure-based drug design, such as substructure search to optimize their structures. Meanwhile, we will develop a novel high-throughput bioassay approach to screen more compounds active against HSP47. The potential application in the treatment of fibrotic diseases of these compounds will be evaluated in cell models. This work should provide useful hints for further development of novel anti-fibrotic drugs.

英文关键词： HSP47 inhibitor;anti-fibrotic;collagen;drug design;binding mechanism