O-GalNAc糖基化是重要的蛋白质修饰，其异常修饰与多种疾病的发生发展密切相关。ppGalNAc-T是蛋白质起始O-GalNAc糖基化的关键调控酶。ppGalNAc-T抑制剂是研究O-GalNAc糖基化的重要工具。目前国际上缺乏抑制效果明显且机理明确的O-GalNAc糖基化抑制剂。我们基于酶联耦合反应原理开发了高通量糖基转移酶抑制剂筛选方法，从约5000种天然化合物中筛选到对抑制ppGalNAc-T酶活和细胞糖基化均有效的化合物分子，该化合物可抑制阿尔兹海默病的病原前体蛋白APP（amyloid precursor protein）的O-GalNAc糖基化并影响其分泌剪切。本项目拟用糖生物学、生物化学、细胞生物学和动物模型实验等方法，系统研究天然化合物小分子抑制剂抑制ppGalNAc-T酶活的分子机制；同时阐明该抑制剂抑制APP糖基化的功能机制，为理解阿尔兹海默病的发病与治疗提供参考。

O-GalNAc glycosylation is an important protein modification and its abnormal state is closely related with a variety of disease. ppGalNAc-T is a key enzyme that regulates the initial step of protein O-GalNAc glycosylation. The inhibitor of ppGalNAc-T is an important tool of researching O-GalNAc glycosylation. However, there is no inhibitor of O-GalNAc glycosylation with obvious effect and distinct inhibitory mechanism internationally. In our previous studies, on the basis of enzyme-linked coupling reaction, we developed a type of high-throughput glycosyltransferase inhibitor screening model. Using this model, we screened approximately 5000 natural compounds and finally identified a natural compound which can effectively inhibit enzyme activity of ppGalNAc-T and glycosylation of cell. We also found that this compound can inhibit O-GalNAc glycosylation on amyloid precursor protein(APP), which is the precursor of pathogenesis-related protein of Alzheimer’s disease, and affect its maturation and processing. In this project, by using methods of glycobiology, enzyme biochemistry, cytobiology and animal models study, we will focus on illuminating the inhibitory molecular mechanism of enzyme activity of ppGalNAc-T and functional mechanism of inhibiting O-GalNAc glycosylation on APP of this natural compound and provide new explanation for the pathogenesis and remedy for Alzheimer's disease.