title: Identification of the first low-molecular-weight inhibitors of matriptase-2.
abstract: 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 K(i) values of 170 and 460 nM, respectively. An inhibitor of the closely related protease matriptase (compound 2, K(i) = 220 nM), with more than 50-fold selectivity over matriptase-2, was also identified.
authors.affiliation: Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, Bonn, Germany.
authors.forename: Mihiret Tekeste
authors.initials: MT
authors.lastname: Sisay
authors.forename: Torsten
authors.initials: T
authors.lastname: Steinmetzer
authors.forename: Marit
authors.initials: M
authors.lastname: Stirnberg
authors.forename: Eva
authors.initials: E
authors.lastname: Maurer
authors.forename: Maya
authors.initials: M
authors.lastname: Hammami
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bajorath
authors.forename: Michael
authors.initials: M
authors.lastname: Gütschow
mesh_terms: D000595:Amino Acid Sequence; D001550:Benzamidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D020134:Catalytic Domain; D002460:Cell Line; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008969:Molecular Sequence Data; D008970:Molecular Weight; D012697:Serine Endopeptidases / Q000737:chemistry / Q000378:metabolism; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D001550:Benzamidines; D004151:Dipeptides; D008565:Membrane Proteins; D013449:Sulfonamides; C551941:benzylsulfonylargininyl-proline-(4-amidinobenzyl)amide; C551942:benzylsulfonylcyclohexylalanyl-proline-(4-amidinobenzyl)amide; D012697:Serine Endopeptidases; C467801:matriptase 2