title: En Route to New Therapeutic Options for Iron Overload Diseases: Matriptase-2 as a Target for Kunitz-Type Inhibitors.
abstract: The cell-surface serine protease matriptase-2 is a critical stimulator of iron absorption by negatively regulating hepcidin, the key hormone of iron homeostasis. Thus, it has attracted much attention as a target in primary and secondary iron overload diseases. Here, we have characterised Kunitz-type inhibitors hepatocyte growth factor activator inhibitor 1 (HAI-1) and HAI-2 as powerful, slow-binding matriptase-2 inhibitors. The binding modes of the matriptase-2-HAI complexes were suggested by molecular modelling. Different assays, including cell-free and cell-based measurements of matriptase-2 activity, determination of inhibition constants and evaluation of matriptase-2 inhibition by analysis of downstream effects in human liver cells, demonstrated that matriptase-2 is an excellent target for Kunitz inhibitors. In particular, HAI-2 is considered a promising scaffold for the design of potent and selective matriptase-2 inhibitors.
authors.affiliation: Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany.
authors.forename: Anna-Madeleine
authors.initials: AM
authors.lastname: Beckmann
authors.affiliation: Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Maurer
authors.affiliation: Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Lülsdorff
authors.affiliation: Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: Wilms
authors.affiliation: Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany.|Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, University of Bonn, Dahlmannstrasse 2, 53113, Bonn, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Furtmann
authors.affiliation: Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, University of Bonn, Dahlmannstrasse 2, 53113, Bonn, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bajorath
authors.affiliation: Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Gütschow
authors.affiliation: Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany. marit.stirnberg@uni-bonn.de.
authors.forename: Marit
authors.initials: M
authors.lastname: Stirnberg
mesh_terms: D002460:Cell Line; D015536:Down-Regulation; D016503:Drug Delivery Systems; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D019190:Iron Overload / Q000188:drug therapy* / Q000201:enzymology; D008099:Liver / Q000201:enzymology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D008958:Models, Molecular; D000072417:Protein Domains / Q000235:genetics; D053491:Proteinase Inhibitory Proteins, Secretory / Q000037:antagonists & inhibitors / Q000737:chemistry; D012697:Serine Endopeptidases / Q000235:genetics
chemical_list: D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D053491:Proteinase Inhibitory Proteins, Secretory; C109149:SPINT1 protein, human; D012697:Serine Endopeptidases; C467801:matriptase 2
keywords: enzymes; inhibitors; iron homeostasis; matriptase-2; membrane proteins