Format

Send to

Choose Destination
ACS Chem Biol. 2010 May 21;5(5):489-97. doi: 10.1021/cb100011u.

Development of GlcNAc-inspired iminocyclitiols as potent and selective N-acetyl-beta-hexosaminidase inhibitors.

Author information

1
Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.

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.

PMID:
20187655
DOI:
10.1021/cb100011u
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for American Chemical Society
Loading ...
Support Center