亚型和底物选择性的O-GlcNAc转移酶抑制剂的发现

O-GlcNAc转移酶（OGT）是一种至关重要的哺乳动物酶，其将单个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OGT抑制剂的研究报道十分有限，目前还没有商品化的高活性、高选择性OGT抑制剂，阻碍了对O-GlcNAc糖基化的功能和调节机制的研究。在本项目中，以OGT为模板，利用实验室自行发展的“捆绑式原位点击化学”策略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，靶标导向合成亚型和底物选择性的OGT抑制剂。进一步阐明不同亚型OGT的生理和病理作用以及选择性识别不同底物的方式，为发展相关疾病的治疗性药物奠定了基础。

O-GlcNAc transferase (OGT), an essential mammalian enzyme, catalyses the transfer of N-acetylglucosamine (GlcNAc) from UDP-N-acetylglucosamine to hydroxyl groups of serines and threonines (Ser/Thr) in proteins. O-GlcNAcylation is widely located in both 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 occurrence and development of numerous critical illnesses. However, reports of OGT inhibitors are very limited and there are no commercial available OGT inhibitors with high activitity and high selectivity, which has impeded the research of function and regulation of O-GlcNAcylation. In this project, target-guided synthesis avoids the dependence of high-throughput activity assays. With the concept of combinatorial chemistry, the novel strategy "tethering in situ click chemistry" employs OGT as a template for self-assembling inhibitors with subtype- and substrate-selectivity from complementary building blocks. The further clarification of physiological/pathological roles of different OGT isoforms and selective recognition of different substrates will establish the foundation for the development of therapeutic drugs for relevant diseases.