Inhibition of human matriptase by eglin c variants

Based on the enzyme specificity of matriptase, a type II transmembrane serine protease (TTSP) overexpressed in epithelial tumors, we screened a cDNA library expressing variants of the protease inhibitor eglin c in order to identify potent matriptase inhibitors. The most potent of these, R1K4'-eglin, which had the wild-type Pro(45) (P1 position) and Tyr(49) (P4' position) residues replaced with Arg and Lys, respectively, led to the production of a selective, high affinity (K-i of 4 nM) and proteolytically stable inhibitor of matriptase. Screening for eglin c variants could yield specific, potent and stable inhibitors to matriptase and to other members of the TTSP family. (c) 2006 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.