A New “Transition-State” Inhibitor Specific for Poly(ADP-ribose) Glycohydrolase

摘要: The degradation of poly(ADP-ribose) in vivo by hydrolysis the glycosidic (1’ ’-2’) ribosyl-ribose linkage is catalyzed glycohydrolase (1,2). Specific inhibitors for this glycosidase have not been available (3), despite suggestions that such would useful pharmacological properties (4). Adenosine diphosphate dihydroxypyrrolidine (ADP-DHP)(Figure 1) was shown to be a potent and selective inhibitor bovine thymus glycohydrolase. Glycohydrolase activity inhibited 50% at 0.3 µM ADP-DHP. ADP-DHP further inhibit Bungarus fasciatus venom NAD competitively, with an dissociation constant (Ki) four-fold lower than product (Kd) adenosine ribose (ADP-ribose). designed mimic structure oxo-carbonium ion intermediate has supported experimentally ADP-ribose nicotinamide vertebrate glycohydrolases. Similar ions are expected as intermediates therefore first series “transition-state” which will produced