Development of GlcNAc-inspired iminocyclitiols as potent and selective N-acetyl-beta-hexosaminidase inhibitors.
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.
Ho
Ching-Wen
CW
Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
Popat
Shinde D
SD
Liu
Ta-Wei
TW
Tsai
Keng-Chang
KC
Ho
Meng-Jung
MJ
Chen
Wei-Hung
WH
Yang
An-Suei
AS
Lin
Chun-Hung
CH
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*
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