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O-连接的N-乙酰葡糖胺糖基化修饰(O-GlcNAcylation)是一种存在于蛋白质Ser/Thr上的翻译后修饰。与磷酸化相似,它参与细胞内的信号传递,并与神经退行性疾病、Ⅱ型糖尿病、癌症等许多疾病的发病机理密切相关。O-连接的N-乙酰葡糖胺水解酶(O-GlcNAcase,OGA)是生物体内唯一水解蛋白质O-GlcNAc修饰的糖苷酶。因此,研究高效、专一的OGA小分子抑制剂是调节细胞中蛋白质O-GlcNAc水平的有效策略,利于阿尔茨海默病等相关神经退行性疾病新型药物的开发。结合本实验室对OGA抑制剂的研究,本文介绍了OGA的结构、催化机理及目前OGA抑制剂的研究进展,讨论了各种抑制剂的构效关系,并对OGA抑制剂的研究前景进行了展望。
O-linked N-acetylglucosamine glycosylation (O-GlcNAcylation) is a post-translational modification present on the protein Ser / Thr. Like phosphorylation, it is involved in intracellular signaling and is closely associated with the pathogenesis of many diseases, such as neurodegenerative diseases, type II diabetes and cancer. O-linked N-acetylglucosamine hydrolase (O-GlcNAcase, OGA) is the only O-GlcNAc-modified glycosidase that hydrolyzes proteins in the body. Therefore, the study of efficient and specific inhibitors of OGA small molecule is an effective strategy for regulating the level of O-GlcNAc protein in cells, which is conducive to the development of new drugs related to neurodegenerative diseases such as Alzheimer’s disease. Combined with our research on OGA inhibitors, this paper introduces the structure and catalytic mechanism of OGA and the current research progress of OGA inhibitors. The structure-activity relationship of various inhibitors is discussed, and the research prospects of OGA inhibitors are discussed Outlook.