College of Pharmacy, State Key Laboratory of Elemento-organic Chemistry, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, PR China.
Bioorg Med Chem Lett. 2012 Nov 15;22(22):6854-7. doi: 10.1016/j.bmcl.2012.09.042. Epub 2012 Sep 23.
Protein O-GlcNAc glycosylation is a ubiquitous post-translational modification in metazoans. O-GlcNAcase (OGA), which is responsible for removing O-GlcNAc from serine or threonine residues, plays a key role in O-GlcNAc metabolism. Potent and selective O-GlcNAcase (OGA) inhibitors are useful tools for investigating the role of this modification in a broad range of cellular processes, and may also serve as drug candidates for treatment of neurodegenerative diseases. Biological screening of the gluco-configured tetrahydroimidazopyridine derivatives identified a compound as a potent and competitive inhibitor of human O-GlcNAcase (OGA) with a K(i) of 5.9 μM, and it also displayed 28-fold selectivity for human OGA over human lysosomal β-hexosaminidase A (Hex A, K(i)=163 μM). In addition, cell-based assay revealed that this compound was cell-permeant and effectively induced cellular hyper-O-GlcNAcylation at 10 μM concentration.
蛋白质 O-GlcNAc 糖基化是后生动物中普遍存在的一种翻译后修饰。负责从丝氨酸或苏氨酸残基上移除 O-GlcNAc 的 O-GlcNAcase（OGA）在 O-GlcNAc 代谢中发挥着关键作用。强效和选择性的 O-GlcNAcase（OGA）抑制剂是研究这种修饰在广泛的细胞过程中的作用的有用工具，也可能成为治疗神经退行性疾病的药物候选物。对葡糖构型的四氢咪唑并吡啶衍生物进行的生物学筛选，发现一种化合物是一种有效的、具有竞争抑制作用的人 O-GlcNAcase（OGA）抑制剂，其 K(i)值为 5.9 μM，对人 OGA 的选择性比人溶酶体 β-己糖胺酶 A（Hex A，K(i)=163 μM）高 28 倍。此外，基于细胞的测定表明，该化合物具有细胞通透性，在 10 μM 浓度下可有效诱导细胞内 O-GlcNAc 过度糖基化。
