半乳呋喃糖基转移酶2抑制剂的设计、合成和活性评价

项目名称： 半乳呋喃糖基转移酶2抑制剂的设计、合成和活性评价

项目编号： No.21302040

项目类型： 青年科学基金项目

立项/批准年度： 2014

项目学科： 数理科学和化学

项目作者： 刘春艳

作者单位： 河北联合大学

项目金额： 25万元

中文摘要： 耐药性结核病的流行是结核病疫情居高不下的重要原因，迫切需要研究和开发具有新结构特点和作用机理的抗结核药物。mAGP是结核杆菌细胞壁主要成分，对于维持细胞壁的完整非常重要。β-(1→5)和β-(1→6)交互连接而成的半乳聚糖是mAGP重要片段，针对参与半乳聚糖生物合成的酶而设计的抗结核药物有望为结核病的治疗提供新的策略。GlfT2是半乳聚糖生物合成中发挥作用的关键酶，且构成半乳聚糖的D-Gal呋喃环形式是结核杆菌所特有，不存在于人体细胞中，因此，研究GlfT2受体类似物抑制剂，有望得到具有高度专一性的抗结核病药物。本项目拟以GlfT2为靶点，利用电子等排和过渡态类似物等理论，设计、合成耐酶解的GlfT2受体碳苷类似物库，并评价其对GlfT2的抑制活性和抗结核活性（包括耐药菌株），旨在寻找具有新结构特征和高活性的GlfT2酶抑制剂，进而发展潜在的对耐药菌有效的抗结核先导化合物。

中文关键词： 碳苷；半乳呋喃糖基转移酶；半乳呋喃糖基转移酶抑制剂；耐药性结核菌株；抗结核活性

英文摘要： The emergence of multi-drug resistant strains of Mycobacterium tuberculosis emphasizes the urgent need for the development of new anti-tubercular agents with novel drug targets. The cell wall of Mycobacterium tuberculosis contains the mycolyl-arabinogalactan-peptidoglycan complex (mAGP), which possesses a core galactan moiety composed of approximately 30 galactofuranosyl resides attached via alternating β-(1→5) and β-(1→6) linkages, and it makes each of the enzymes involved in galactofuranoside biosynthesis a potential therapeutic target. Galactofuranosyltransferase 2 (GlfT2) plays a crucial role in galactofuranosyl resides' biosynthesis, and a key feature of galactose units in mycobacteria is that they are in the furanose forms, which are not found in animal systems. This could lead to the development of inhibitors of this enzymes. We plan to synthesize a library of C-glycosides mimicking the Galf-β-(1→5)-Galf substructures of mycobacterial arabinogalactan to investigate the interaction of these hydrolytically stable disaccharide analogues with the enzyme GlfT2 and their antitubercular activity, which could find antitubercular lead compounds with new structural characteristics.

英文关键词： C-glycoside；galactofuranosyltransferase；Galactofuranosyltransferase inhibitor；drug resistant strains of M. tuberculosis；antituberculosis