O-GlcNAcase抑制剂  

O-GlcNAcase Inhibitors

作　　者：李铁海[1] 郭利娜[1] 李中华[1] 王佳佳[1] 李静 赵炜[1] 

机构地区：[1]南开大学药学院药物化学生物学国家重点实验室,天津300071

出　　处：《化学进展》2011年第8期1657-1664,共8页Progress in Chemistry

基　　金：国家重点基础研究发展计划(973)项目(No.2007CB914403);国家自然科学基金项目(No.91013013;20802037;31000371)资助

摘　　要：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-GlcNAcylation is a newly discovered protein post-translational modification on Ser/Thr. Similar to phosphorylation, O-GlcNAcylation plays an important role in cell signal transduction and may be associated with many human diseases such as degenerative diseases, type I1 diabetes and cancer. O-linked-N-acetylglucosidase （ O-GlcNAcase, OGA） is the only glycoside hydrolase catalyzing the hydrolytic cleavage of O-linked-N-acetylglueo- samine （O-GIcNAc） from serine and threonine residues of proteins. So using potent and specific small-molecular OGA inhibitors is the most direct approach for modulating protein O-GlcNAcylation levels in cell. Furthermore, these potent, selective inhibitors offer motivation for the generation of new drugs for the therapy of Alzheimer＇s disease （AD） and the associated degenerative diseases. According to the research on OGA inhibitors in our lab, the structure and the catalytic mechanism of OGA and related OGA inhibitors are introduced. In addition, the structure and activity relationships of OGA inhibitors and the perspective of the study on OGA inhibitors are also discussed.

关 键 词：O-GLCNACASE 修饰 O-GLCNACASE 抑制剂 

分 类 号：O629.1[理学—有机化学] Q53[理学—化学]