Selective inhibition of human mast cell tryptase by gabexate mesylate, an antiproteinase drug

Gabexate mesylate is a non-antigenic synthetic inhibitor of trypsin-like se rine proteinases that is therapeutically used in the treatment of pancreati tis and disseminated intravascular coagulation and as a regional anticoagul ant for hemodialysis. Considering the structural similarity between gabexat e mesylate and arginine-based inhibitors of trypsin-like serine proteinases . the effect of gabexate mesylate on human and bovine mast cell tryptase ac tion 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, gabexat e mesylate inhibited the fibrinogenolytic activity of human tryptase. On th e basis of the available x-ray crystal structure of human tryptase, the pos sible binding mode of gabexate mesylate to human and bovine tryptase was an alyzed. Human tryptase inhibition by gabexate mesylate may account for the reported prevention of inflammation, erosion, and ulceration of skin and mu cosae. (C) 2001 Elsevier Science Inc. All rights reserved.