Gitlin-Domagalska Agata, Dębowski Dawid, Łęgowska Anna, Stirnberg Marit, Okońska Joanna, Gütschow Michael, Rolka Krzysztof
Department of Molecular Biochemistry, Faculty of Chemistry, University of Gdansk, ul. Wita Stwosza 63, Gdansk, 80-308, Poland.
Pharmaceutical Institute, University of Bonn, An der Immenburg 4, Bonn, 53121, Germany.
Biopolymers. 2017 Nov;108(6). doi: 10.1002/bip.23031.
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 , Arg , His ]SFTI-1, with a K value of 15 nm was obtained.
Matriptase-2在将人体铁浓度维持在狭窄的生理范围内起着关键作用。降低matriptase-2蛋白水解活性的机会可能为治疗铁过载疾病（如遗传性血色素沉着症和地中海贫血）开辟新的途径。在此，我们展示了23种旨在抑制人matriptase-2的胰蛋白酶抑制剂SFTI-1的新类似物。研究了Gly1Lys、Ile10Arg和Phe12His修饰以及在P1或P1和P4位置引入Narg的影响。与先前报道的肽一起，对选定的肽进行了进一步分析，以检测它们对相关人类蛋白酶（即matriptase-1、纤溶酶、凝血酶和胰蛋白酶）的抑制活性。获得了一种matriptase-2的高效抑制剂，双环[Arg ，Arg ，His ]SFTI-1，其K值为15 nm。
