O-GlcNAc转移酶抑制剂的发现

项目名称： O-GlcNAc转移酶抑制剂的发现

项目编号： No.21302182

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： 王玥

作者单位： 中国科学院大学

项目金额： 25万元

中文摘要： O-GlcNAc转移酶是一种哺乳动物必需的酶，其将单个的N-乙酰氨基葡萄糖（GlcNAc）以O-糖苷键连接到蛋白质的丝氨酸和苏氨酸（Ser / Thr）羟基上。O-GlcNAc糖基化在细胞质和细胞核中广泛地存在，这种蛋白质的翻译后修饰对细胞内的许多信号通路具有调节作用，并与多种重大疾病的发生和发展密切相关。然而，针对O-GlcNAc转移酶抑制剂的研究报道十分有限，目前活性最好的抑制剂IC50仅在微摩尔水平。发现O-GlcNAc转移酶抑制剂的一个主要障碍是缺少快速简单的O-GlcNAc转移酶活性测定方法。在本项目中，以O-GlcNAc转移酶为模板，利用原位点击化学使合适的构建模块自组装，避免了高通量活性测定方法的依赖，以组合化学的理念，靶标导向合成高活性的抑制剂。这对于阐明O-GlcNAc糖基化的功能和调节机制有重要意义，为发展相关疾病的治疗性药物奠定了基础。

中文关键词： O-GlcNAc；O-GlcNAc转移酶；酶抑制剂；原位点击化学；靶标导向合成

英文摘要： O-GlcNAc transferase (OGT), one of essential mammalian enzymes, catalyses the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine (UDP-GlcNAc) to hydroxyl groups of serines and threonines (Ser / Thr) in proteins. O-GlcNAcylation is widely located in cytoplasm and nucleus. This kind of protein post-translational modification is involved in the regulation of many cellular signaling pathways and closely associated with the occurrences and developments of numerous critical illnesses. However, research reports of OGT inhibitors are very limited and the half inhibitory concentration (IC50) of the best inhibitor is in a micromolar range. The lack of a rapid and simple method for monitoring OGT activity has impeded the efficient discovery of potent OGT inhibitors. In this project, target-guided synthesis avoids the dependence of high-throughput activity assays. With the concept of combinatorial chemistry, in situ click chemistry approach employs OGT as a template for self-assembling inhibitors with high activities from complementary building blocks. This will be significant for the clarifications of function and regulatory mechanism of O-GlcNAcylation and establish the foundation for the development of therapeutic drugs for relevant diseases.

英文关键词： O-GlcNAc；O-GlcNAc transferase；enzyme inhibitors；in situ click chemistry；target-guided synthesis