Development of GlcNAc-Inspired Iminocyclitiols as Potent and Selective N-Acetyl-β-Hexosaminidase Inhibitors
Development of GlcNAc-Inspired Iminocyclitiols as Potent and Selective N-Acetyl-β-Hexosaminidase Inhibitors
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DOI：
10.1021/cb100011u
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发表时间：
2010-05-01
影响因子：
4
通讯作者：
Lin, Chun-Hung
中科院分区：
文献类型：
--
作者：
Ho, Ching-Wen;Popat, Shinde D.;Lin, Chun-Hung
人类N-乙酰-β-氨基己糖苷酶（Hex）同工酶被认为是药物发现的重要靶标。它们与骨关节炎直接相关，因为Hex是软骨细胞释放的降解糖胺聚糖的主要糖苷酶。Hex也与溶酶体贮积症有关。我们报告的发现GlcNAc型iminocyclitiols作为有效的和选择性的Hex抑制剂，可能有助于获得额外的静电和疏水相互作用。最有效的抑制剂对人Hex B的Ki为0.69 nM，并且对Hex B的选择性比对类似的人酶O-GlcNAc酶的选择性高2.5 × 10（5）倍。这些糖苷酶抑制剂显示调节糖脂的细胞内水平，包括神经节苷脂-GM 2和去唾液酸神经节苷脂-GM 2。
Human N-acetyl-beta-hexosaminidase (Hex) isozymes are considered to be important targets for drug discovery. They are directly linked to osteoarthritis because Hex is the predominant glycosidase released by chondrocytes to degrade glycosaminoglycan. Hex is also associated with lysosomal storage disorders. We report the discovery of GlcNAc-type iminocyclitiols as potent and selective Hex inhibitors, likely contributed by the gain of extra electrostatic and hydrophobic interactions. The most potent inhibitor had a K-i of 0.69 nM against human Hex B and was 2.5 x 10(5) times more selective for Hex B than for a similar human enzyme O-GlcNAcase. These glycosidase inhibitors were shown to modulate intracellular levels of glycolipids, including ganglioside-GM2 and asialoganglioside-GM2.