title: Irreversible inhibition of serine proteases by peptidyl derivatives of alpha-aminoalkylphosphonate diphenyl esters.
abstract: Peptidyl alpha-aminoalkylphosphonate diphenyl esters have been synthesized and shown to be effective inhibitors of serine proteases. Extending the peptide chain from a single alpha-aminoalkylphosphonate residue (kobs/[I] = 2.5-260 M-1 s-1) to a tripeptide or tetrapeptide derivative (kobs/[I] = 7,000-17,000 M-1 s-1) resulted in 65-2800 improvement in inhibitory potency and increased specificity. The rate of inactivation of chymotrypsin by MeO-Suc-Ala-Ala-Pro-HNCH(CH2Ph)P(O)(OPh)2 was decreased 5 fold in the presence of the substrate Suc-Val-Pro-Phe-NA (0.119 mM). Phosphonylated serine proteases are extremely stable since the half-life for reactivation was greater than 48 hrs for the inhibited elastases and at least 10 hrs for chymotrypsin.
authors.affiliation: School of Chemistry, Georgia Institute of Technology, Atlanta 30332.
authors.forename: J
authors.initials: J
authors.lastname: Oleksyszyn
authors.forename: J C
authors.initials: JC
authors.lastname: Powers
mesh_terms: D001665:Binding Sites; D002918:Chymotrypsin / Q000037:antagonists & inhibitors; D004795:Enzyme Stability; D006801:Humans; D007700:Kinetics; D009842:Oligopeptides / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors; D010455:Peptides / Q000494:pharmacology*; D015842:Serine Proteinase Inhibitors; D013379:Substrate Specificity
chemical_list: D009842:Oligopeptides; D009943:Organophosphorus Compounds; D010455:Peptides; D015842:Serine Proteinase Inhibitors; D002918:Chymotrypsin; D010196:Pancreatic Elastase