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Design and chemical syntheses of potent matriptase‐2 inhibitors based on trypsin inhibitor SFTI‐1 isolated from sunflower seeds
Author(s) -
GitlinDomagalska Agata,
Dębowski Dawid,
Łęgowska Anna,
Stirnberg Marit,
Okońska Joanna,
Gütschow Michael,
Rolka Krzysztof
Publication year - 2017
Publication title -
peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/bip.23031
Subject(s) - proteases , chemistry , trypsin inhibitor , trypsin , biochemistry , plasmin , enzyme , c1 inhibitor , biology , immunology , angioedema
Matriptase‐2 plays a pivotal role in keeping iron concentrations within a narrow physiological range in humans. The opportunity to reduce matriptase‐2 proteolytic activity may open a novel possibility to treat iron overload diseases, such as hereditary hemochromatosis and thalassemia. Here, we present 23 new analogues of trypsin inhibitor SFTI‐1 designed to inhibit human matriptase‐2. Influence of the modifications Gly1Lys, Ile10Arg, and Phe12His, as well as the introduction of Narg in P1 or P1 and P4 positions were examined. Selected peptides were further analyzed, together with previously reported peptides, for their inhibitory activity against related human proteases, that are, matriptase‐1, plasmin, thrombin and trypsin. A highly potent inhibitor of matriptase‐2, the bicycylic [Arg 5 , Arg 10 , His 12 ]SFTI‐1, with a K i value of 15 n m was obtained.