Inhibitors of Matriptase-2 Based on the Trypsin Inhibitor SFTI-1.

A series of 17 new analogues of trypsin inhibitor SFTI-1 were designed and synthesized to obtain matriptase-2 inhibitors. A number of the modified bicyclic peptides displayed much higher affinity towards matriptase-2 than towards the highly homologous matriptase-1. Replacement of Lys5 by Arg in the wild-type SFTI-1 led to an 11-fold increase in the matriptase-2 inhibitory activity. Replacement of Arg2 by its enantiomer (D-arginine) slightly lowered the inhibition of matriptase-2, but almost completely abolished the affinity towards matriptase-1, thus yielding the most selective matriptase-2 inhibitor. This is the first report describing inhibitors of the recently discovered matriptase-2 based on the SFTI-1 structure. The results showed that SFTI-1 is a promising scaffold for the design of potent and selective inhibitors of this enzyme.