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.

Graphical abstractBisubstrate analog inhibitors in which a nicotinamide mimetic is attached to a series of structurally diversified guanidines (arginine mimic) were synthesized and evaluated for inhibition of cholera toxin. Our results demonstrated that the mechanism-based bisubstrate inhibitors were up to 1400-fold more potent than 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.Figure optionsDownload full-size imageDownload as PowerPoint slide