title: Selective inhibition of human mast cell tryptase by gabexate mesylate, an antiproteinase drug.
abstract: Gabexate mesylate is a non-antigenic synthetic inhibitor of trypsin-like serine proteinases that is therapeutically used in the treatment of pancreatitis and disseminated intravascular coagulation and as a regional anticoagulant for hemodialysis. Considering the structural similarity between gabexate mesylate and arginine-based inhibitors of trypsin-like serine proteinases, the effect of gabexate mesylate on human and bovine mast cell tryptase action was investigated. Values of the inhibition constant (K(i)) for gabexate mesylate binding to human and bovine tryptase were 3.4 x 10(-9) M and 1.8 x 10(-7) M (at pH 7.4 and 37.0 degrees ), respectively. Furthermore, gabexate mesylate inhibited the fibrinogenolytic activity of human tryptase. On the basis of the available x-ray crystal structure of human tryptase, the possible binding mode of gabexate mesylate to human and bovine tryptase was analyzed. Human tryptase inhibition by gabexate mesylate may account for the reported prevention of inflammation, erosion, and ulceration of skin and mucosae.
authors.affiliation: Department of Experimental Medicine and Biochemical Sciences, University of Rome 'Tor Vergata', Via di Tor Vergata 135, I-00133, Rome, Italy. erba@uniroma2.it
authors.forename: F
authors.initials: F
authors.lastname: Erba
authors.forename: L
authors.initials: L
authors.lastname: Fiorucci
authors.forename: S
authors.initials: S
authors.lastname: Pascarella
authors.forename: E
authors.initials: E
authors.lastname: Menegatti
authors.forename: P
authors.initials: P
authors.lastname: Ascenzi
authors.forename: F
authors.initials: F
authors.lastname: Ascoli
mesh_terms: D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D016670:Gabexate / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008407:Mast Cells / Q000187:drug effects* / Q000201:enzymology; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013045:Species Specificity; D013329:Structure-Activity Relationship; D053802:Tryptases
chemical_list: D015842:Serine Proteinase Inhibitors; D016670:Gabexate; D012697:Serine Endopeptidases; D053802:Tryptases