苦参酸类活性小分子探针的化学构建及其全新抗HCV机制第一靶标的探索

项目名称： 苦参酸类活性小分子探针的化学构建及其全新抗HCV机制第一靶标的探索

项目编号： No.21472246

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 环境科学、安全科学

项目作者： 宋丹青

作者单位： 中国医学科学院医药生物技术研究所

项目金额： 90万元

中文摘要： 我们自主创新对甲氧苄苦参酸(DM122)是一全新结构、全新机理的抗HCV候选物，通过下调宿主肝细胞热休克应急蛋白 70（Hsc70）的基因表达而发挥作用，具有不易诱导耐药、安全性高等多个优势。但其抗HCV第一靶标以及化学生物学机制等尚不清楚。 本项目拟在一系列原创性工作基础上，针对DM122全新抗HCV机制，通过生物素亲和标记、罗丹明B荧光标记的两类DM122探针分子的结构修饰与优化，优选出特异性下调Hsc70表达的活性探针分子。并以此目标探针为化学工具，进行DM122抗HCV第一靶的标记、分离、纯化、鉴别及确认等研究，以期获得抗HCV药物全新药物靶点。以此为靶点抗HCV药物具有不易诱导耐药的优势，尤其适宜于HCV患者长期服用。进而阐明 DM122抗HCV化学生物学机制，完成其抗HCV整体研究，从根本上克服抗 HCV 药物耐药难题提供全新策略，使我国抗HCV创新药物研究跨入世界前沿。

中文关键词： 苦参酸；抗丙型肝炎病毒；分子探针；构效关系；第一靶标

英文摘要： Our innovative N-p-methoxymatrinic acid (DM122) was an ideal anti-HCV candidate bearing a novel structure skeleton and novel action of mode, it played a part in down-regulating the host hepatic heat stress connate 70 (Hsc 70) gene expression in host liver cell and thus had the advantages of being rarely drug-resistant and highly safe. However, its primary target protein and chemical biology mechanism were still unknown. Based on these original work, focused on the novel anti-HCV mechanism of DM122, two classes of DM122 probe molecules tagged by biotin and rhodamine B respectively will be designed and optimized in the titled project, and the active probe molecules that can specifically down-regulate Hsc 70 expression will be selected out. Next, these target probes will be applied as chemical tools to carry out a whole study of the labeling, separation, purification, identification and verification of DM122's anti-HCV first target, so as to find out a novel anti-HCV target protein. The anti-HCV drugs targeted on the gained protein are unlikely to induce drug-resistance, thus will surely meet the need of a long-term treatment of HCV. Moreover, the study will illustrate DM122's anti-HCV chemical biology mechanism and finally complete its whole anti-HCV study. The study provides a new strategy in overcoming anti-HCV drug resistance fundamentally, and will bring China's innovative anti-HCV drug to reach the frontier of the world.

英文关键词： matrinic acid;anti-HCV;molecule probe;structure-activity relationship;primary target