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 Pro⁴⁵ (P1 position) and Tyr⁴⁹ (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.