title: Mechanistic studies on the inactivation of papain by epoxysuccinyl inhibitors.
abstract: Analogs of the epoxysuccinyl peptide cysteine proteinase inhibitor, EP-475 (2a), in which the free carboxylate has been replaced by hydroxamic acid, amide, methyl ketone, hydroxyl, and ethyl ester functionalities, have been synthesized. Individual rate constants of inhibition of papain were determined for these inhibitors. The results show that a carbonyl-containing functionality is necessary for good activity. The pH dependence of the inhibition of papain was determined for a nonionizable EP-475 (2a) analog; inhibition was found to depend on two acidic ionizations (pKas of 3.93 and 4.09) of papain. Implications for the mechanism of action of epoxysuccinyl peptides with papain are discussed.
authors.affiliation: School of Pharmacy, University of Wisconsin, Madison 53705, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Meara
authors.forename: D H
authors.initials: DH
authors.lastname: Rich
mesh_terms: D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004852:Epoxy Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010206:Papain / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013386:Succinates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D015853:Cysteine Proteinase Inhibitors; D004852:Epoxy Compounds; D013386:Succinates; D010206:Papain