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Chembiochem. 2016 Apr 1;17(7):595-604. doi: 10.1002/cbic.201500651. Epub 2016 Feb 16.

En Route to New Therapeutic Options for Iron Overload Diseases: Matriptase-2 as a Target for Kunitz-Type Inhibitors.

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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.
Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany.


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.


enzymes; inhibitors; iron homeostasis; matriptase-2; membrane proteins

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