Design, synthesis, and evaluation of bisubstrate analog inhibitors of cholera toxin.
Bisubstrate analog inhibitors in which a nicotinamide mimic is attached to a series of structurally diversified guanidines (arginine mimics) were synthesized and evaluated for inhibition of cholera toxin. The mechanism-based bisubstrate inhibitors were up to 1400-fold more potent than the natural substrate NAD+ and 400-fold more potent than the artificial substrate diethylamino (benzylidine-amino)guanidine (DEABAG) in an assay toward an intrinsically active mutant of wild-type cholera toxin.
Department of Chemistry, University of Washington, PO Box 351700, Seattle, WA 98195, USA. windzgt@gmail.com
Guangtao
G
Zhang
D000992:Antitoxins / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D002772:Cholera Toxin / Q000037:antagonists & inhibitors*; D015195:Drug Design; D019791:Guanidine / Q000737:chemistry; D006160:Guanosine Triphosphate / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008956:Models, Chemical; D008968:Molecular Conformation; D009243:NAD / Q000737:chemistry; D009536:Niacinamide / Q000737:chemistry; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D000992:Antitoxins; D009243:NAD; D009536:Niacinamide; D006160:Guanosine Triphosphate; D002772:Cholera Toxin; D019791:Guanidine