Division of Molecular Microbiology, College of Life Sciences, University of Dundee, Dundee, Scotland, UK.
FEBS Lett. 2010 Feb 19;584(4):694-700. doi: 10.1016/j.febslet.2009.12.020. Epub 2009 Dec 16.
O-GlcNAcylation is an essential posttranslational modification in metazoa. Modulation of O-GlcNAc levels with small molecule inhibitors of O-GlcNAc hydrolase (OGA) is a useful strategy to probe the role of this modification in a range of cellular processes. Here we report the discovery of novel, low molecular weight and drug-like O-GlcNAcase inhibitor scaffolds by high-throughput screening. Kinetic and X-ray crystallographic analyses of the binding modes with human/bacterial O-GlcNAcases identify some of these as competitive inhibitors. Comparative kinetic experiments with the mechanistically related human lysosomal hexosaminidases reveal that three of the inhibitor scaffolds show selectivity towards human OGA. These scaffolds provide attractive starting points for the development of non-carbohydrate, drug-like OGA inhibitors.
O-GlcNAc ylation 是后生动物中一种重要的翻译后修饰。用小分子 O-GlcNAc 水解酶 (OGA) 的抑制剂来调节 O-GlcNAc 水平，是一种研究这种修饰在一系列细胞过程中作用的有用策略。在这里，我们通过高通量筛选报告了新型、低分子量和类药 O-GlcNAcase 抑制剂支架的发现。与人和细菌 O-GlcNAcases 的结合模式的动力学和 X 射线晶体学分析将其中一些确定为竞争性抑制剂。与机制上相关的人溶酶体己糖胺酶的比较动力学实验表明，三种抑制剂支架对人 OGA 具有选择性。这些支架为开发非碳水化合物、类药 OGA 抑制剂提供了有吸引力的起点。
