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Identification of the First Low-Molecular-Weight Inhibitors of Matriptase-2

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journal contribution
posted on 2010-08-12, 00:00 authored by Mihiret Tekeste Sisay, Torsten Steinmetzer, Marit Stirnberg, Eva Maurer, Maya Hammami, Jürgen Bajorath, Michael Gütschow
As recently discovered, matriptase-2, a type II transmembrane serine protease, plays a crucial role in body iron homeostasis by down-regulating hepcidin expression, which results in increased iron levels. Thus, matriptase-2 represents a novel target for the development of enzyme inhibitors potentially useful for the treatment of systemic iron overload (hemochromatosis). A comparative three-dimensional model of the catalytic domain of matriptase-2 was generated and utilized for structure-based virtual screening in combination with similarity searching and knowledge-based compound design. Two N-protected dipeptide amides containing a 4-amidinobenzylamide as P1 residue (compounds 1 and 3) were identified as the first small molecule inhibitors of matriptase-2 with Ki values of 170 and 460 nM, respectively. An inhibitor of the closely related protease matriptase (compound 2, Ki = 220 nM), with more than 50-fold selectivity over matriptase-2, was also identified.