Development of GlcNAc-Inspired Iminocyclitiols as Potent and Selective N-Acetyl-beta-Hexosaminidase Inhibitors
Resource
ACS CHEMICAL BIOLOGY, 5(5), 489-497
Journal
ACS CHEMICAL BIOLOGY
Journal Volume
5
Journal Issue
5
Pages
489-497
Date Issued
2010
Date
2010
Author(s)
Ho, Ching-Wen
Popat, Shinde D.
Liu, Ta-Wei
Tsai, Keng-Chang
Ho, Meng-Jung
Chen, Wei-Hung
Yang, An-Suei
Lin, Chun-Hung
Abstract
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.
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Type
journal article
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