糖链的唾液酸化修饰是在唾液酸转移酶的催化下完成的，在生命过程中发挥着重要的作用；然而，目前人们对于细胞中特定糖链的唾液酸化修饰的功能和机制认识不清，主要原因是缺乏有效的化学生物学手段。本项目拟在课题组前期研究工作基础上，模拟唾液酸转移酶催化反应的过渡态，优化抑制剂的分子结构；进一步以动态组合化学的理念，基于原位点击化学的靶标导向合成策略，筛选出新的抑制剂探针分子；然后对合成的目标物进行分子水平、细胞水平的酶抑制活性评价，以期发现新的活性高、能透过细胞膜的唾液酸转移酶抑制剂，从而为唾液酸化修饰相关的功能和机制的理解提供新的有效的探针分子。

Sialylation of glycans is catalyzed by sialyltransferases, and it plays important roles in life processes. However, the functions and mechanisms of sialylation of certain glycans on cells have not yet been understood, due to the shortage of effective chemical tools. Based on our previous achievements, in this proposal we plan to mimic the transition-state of sialyltransferase-catalyzed reaction, and to optimize the molecular structures of inhibitors. Furthermore, by virtue of the concept of dynamic combinatorial chemistry, we want to target-guidedly synthesize and screen new inhibitor probes by in situ click chemistry. The inhibitory activities of these synthesized target compounds against enzymes will be evaluated on both molecular levels and cellular levels. We want to find new sialyltransferase inhibitors with high potency and good cell membrane-penetration ability, thus providing new effective probes for the understanding of functions and mechanisms of sialylation-related events.