Immucillins in custom catalytic-site cavities

Neighboring-group participation in the reaction catalyzed by purine nucleoside phosphorylase involves a compression mode between the 5′- and 4′-ribosyl oxygens, facilitated by His257. The His257Gly mutant opens a space in the catalytic site. Hydrophobic 5′-substituted Immucillins are transition-state analogue inhibitors of this mutant enzyme. Dissociation constants as low as 2 pM are achieved, with Km/Kd as high as 400,000,000.