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化学进展 2011, Vol. 23 Issue (8): 1657-1664 前一篇   后一篇

• 综述与评论 •

O-GlcNAcase抑制剂

李铁海, 郭利娜, 李中华, 王佳佳, 李静*, 赵炜*   

  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
  • 收稿日期:2010-11-01 修回日期:2011-02-01 出版日期:2011-08-24 发布日期:2011-07-25
  • 通讯作者: 李静, 赵炜 E-mail:jinglink@nankai.edu.cn; wzhao@nankai.edu.cn
  • 基金资助:

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

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O-GlcNAcase Inhibitors

Li Tiehai, Guo Lina, Li Zhonghua, Wang Jiajia, Li Jing*, Zhao Wei*   

  1. College of Pharmacy, The State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China
  • Received:2010-11-01 Revised:2011-02-01 Online:2011-08-24 Published:2011-07-25

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。

关键词： O-GlcNAc修饰, O-GlcNAcase, 抑制剂

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 Ⅱ diabetes and cancer. O-linked-N-acetylglucosidase (O-GlcNAcase, OGA) is the only glycoside hydrolase catalyzing the hydrolytic cleavage of O-linked-N-acetylgluco-samine (O-GlcNAc) 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.

Contents
1 Introduction
2 Structure and catalytic mechanism of OGA
3 OGA inhibitors
3.1 Streptozotocin
3.2 PUGNAc and its analogues
3.3 NAG-thiazolin and its analogues
3.4 Nagstain and its analogues
3.5 Iminocyclitiols
3.6 Other OGA inhibitors
4 Conclusion and perspective

Key words: O-GlcNAc modification, O-GlcNAcase(OGA), inhibitors

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O-GlcNAcase抑制剂