title: Development of GlcNAc-inspired iminocyclitiols as potent and selective N-acetyl-beta-hexosaminidase inhibitors.
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.
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
authors.forename: Ching-Wen
authors.initials: CW
authors.lastname: Ho
authors.forename: Shinde D
authors.initials: SD
authors.lastname: Popat
authors.forename: Ta-Wei
authors.initials: TW
authors.lastname: Liu
authors.forename: Keng-Chang
authors.initials: KC
authors.lastname: Tsai
authors.forename: Meng-Jung
authors.initials: MJ
authors.lastname: Ho
authors.forename: Wei-Hung
authors.initials: WH
authors.lastname: Chen
authors.forename: An-Suei
authors.initials: AS
authors.lastname: Yang
authors.forename: Chun-Hung
authors.initials: CH
authors.lastname: Lin
mesh_terms: D000117:Acetylglucosamine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D005678:G(M2) Ganglioside / Q000378:metabolism; D006028:Glycosphingolipids / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007700:Kinetics; D051379:Mice; D017628:Microglia / Q000378:metabolism; D008958:Models, Molecular; D010091:Oximes / Q000494:pharmacology; D048448:Phenylcarbamates / Q000494:pharmacology; D013311:Streptozocin / Q000494:pharmacology; D001619:beta-N-Acetylhexosaminidases / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D006028:Glycosphingolipids; D010091:Oximes; D048448:Phenylcarbamates; C068836:N-acetylglucosaminono-1,5-lactone O-(phenylcarbamoyl)oxime; D005678:G(M2) Ganglioside; D013311:Streptozocin; C110628:hexosaminidase C; D001619:beta-N-Acetylhexosaminidases; D000117:Acetylglucosamine