title: Synthesis and kinetic evaluation of peptide alpha-keto-beta-aldehyde-based inhibitors of trypsin-like serine proteases.
abstract: New, synthetic peptide analogues bearing a C-terminal basic alpha-keto-beta-aldehyde moiety were prepared as novel inhibitors of the trypsin-like serine proteases. The compounds, Ac-Leu-Leu-Arg-COCHO, Ac-Arg-Gln-Arg-COCHO and Boc-Val-Leu-Lys-COCHO were evaluated kinetically against trypsin and three other trypsin-like serine proteases, tryptase, plasmin and thrombin, all of which are implicated as mediators of important disease processes. Results illustrate that alpha-keto-beta-aldehydes are potent inhibitors, with similar potency to comparable peptide aldehydes, and intriguingly, appearto act, in some instances, by a novel mechanism of action. Ac-Leu-Leu-Arg-COCHO, an analogue of the natural product leupeptin, is a potent, tight-binding inhibitor of trypsin (Ki(final) = 1.9 microM), plasmin (Ki(final) = 4.9 microM) and tryptase (Ki(final) = 1.2 microM) and an irreversible inactivator of thrombin (k2nd 4,500 M(-1).min(-1)). Boc-Val-Leu-Lys-COCHO was found to be a tight-binding inhibitor of its target protease plasmin (Ki(final) = 3.1 microM) and was inactive against thrombin. Ac-Arg-Gln-Arg-COCHO was a slow-binding inhibitor of tryptase (Ki(final) = 1.6 microM) and also irreversibly inactivated trypsin (k2nd = 8,920 M(-1) min(-1)). Peptides or peptidomimetics with a C-terminal basic alpha-keto-beta-aldehyde function thus provide a useful new molecular template for the development of new therapeutic agents against a wide range of disorders, such as coagulopathies and asthma, which may be mediated by the aberrant activity of trypsin-like serine proteases.
authors.affiliation: Division of Biomedicinal Chemistry, School of Pharmacy, Medical Biology Centre, The Queen's University of Belfast, Northern Ireland. j.lynas@uqub.ac.uk
authors.forename: J F
authors.initials: JF
authors.lastname: Lynas
authors.forename: S L
authors.initials: SL
authors.lastname: Martin
authors.forename: B
authors.initials: B
authors.lastname: Walker
mesh_terms: D000447:Aldehydes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001249:Asthma / Q000188:drug therapy / Q000503:physiopathology; D001778:Blood Coagulation Disorders / Q000188:drug therapy / Q000503:physiopathology; D006801:Humans; D007700:Kinetics; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000378:metabolism*
chemical_list: D000447:Aldehydes; D010446:Peptide Fragments; C114880:trypsin-like serine protease; D012697:Serine Endopeptidases