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Development of GlcNAc-Inspired Iminocyclitiols as Potent and Selective N-Acetyl-β-Hexosaminidase Inhibitors

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Ching-Wen Ho†‡§, Shinde D. Popat†, Ta-Wei Liu†, Keng-Chang Tsai

, Meng-Jung Ho†

, Wei-Hung Chen†, An-Suei Yang

‡ and Chun-Hung Lin†

‡

^† Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan

^‡ Chemical Biology and Molecular Biophysics, Taiwan International Graduate Program, Academia Sinica, Taipei, Taiwan

^§ Department of Chemistry, National Tsing-Hua University, Hsin-Chu, Taiwan

The Genomics Research Center, Academia Sinica, Taipei, Taiwan

Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan

ACS Chem. Biol., 2010, 5 (5), pp 489–497

DOI: 10.1021/cb100011u

Publication Date (Web): February 27, 2010

* Corresponding author, chunhung@gate.sinica.edu.tw.

Section:

Pharmacology

Abstract

Human N-acetyl-β-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 × 10⁵ 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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This article has been cited by 1 ACS Journal articles (1 most recent appear below).

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