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Inhibitors of Matriptase‐2 Based on the Trypsin Inhibitor SFTI‐1
Author(s) -
Gitlin Agata,
Dębowski Dawid,
Kartalia,
Łęgowska Anna,
Stirnberg Marit,
Gütschow Michael,
Rolka Krzysztof
Publication year - 2015
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201500200
Subject(s) - chemistry , enzyme , biochemistry , arginine , trypsin , amino acid
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.