A series of novel, selective matriptase inhibitors

BACKGROUNDEven though both type II transmembrane serine proteases (TTSPs), matriptase-1 (MT1) and matriptase-2 (MT2) share significant structural similarity and substrate specificity, they differ in biological functions [1]. RESULTS METHODS CONCLUSIONSMT1 -MT2 active site superimposition MT1 widely expressed in all types of epithelial tissues maintains integrity of epithelial tissues increased expression reported in epithelial cancers in breast and prostate cancers increased expression is considered as a predictive factor of poor disease prognosis MT2 mostly localized in the liver regulates iron homeostasis differently from MT1, a positive correlation between its increased level and prognosis in the breast cancer patients We have shown recently, that the gradual shortening of the primary structure of Chinese frog-skin derived inhibitor (HV-BBI, Huia versabilis Bowman-Birk inhibitor, 18amino acids) led to strong non-covalent, disulfide-bridged MT1 inhibitor (13-amino acids) with C-terminal amide group [2].Gly 1 -Cys-Trp-Thr-Lys-Ser-Ile-Pro-Pro-Arg-Pro-Cys-Phe 13 -NH 2 strong MT1 inhibitor K i = 8.5 nM weak MT2 inhibitor K i = 7900 nM Moreover, this inhibitor has presented unprecedented specificity toward MT1 as compared to MT2.The K i value was almost 1000-times lower for MT1 than for MT2.To the best of our knowledge, such significant selectivity, combined with high inhibitory potency, have not been reported so far, for any known MT1 inhibitors.Name Inhibitor sequence H Gly-Cys(&)-Trp-Thr-Lys-Ser-Ile-Pro-Pro-Arg-Pro-Cys(&)-Phe-NH 2 H-1 Gly-Cys(&)-Trp-Thr-Lys-Ser-Ile-Pro-Pro-Arg-Pro-Cys(&)-DPhe-NH 2 H-2 Gly-Cys(&)-Trp-Thr-Lys-Ser-Ile-Pro-Pro-Arg-Pro-Cys(&)-diPhe-NH 2 H-3 Gly-Cys(&)-Trp-Thr-