No 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.

The cover picture shows the proposed regulatory mechanism of the type II transmembrane serine protease matriptase‐2 predominantly expressed at the surface of hepatocytes. Human matriptase‐2 is a critical stimulator of iron absorption by negatively regulating hepcidin, the key hormone of iron homeostasis that controls dietary iron uptake and the release of iron from macrophages and hepatocytes. This involves the BMP/SMAD signalling pathway through cleavage of the BMP co‐receptor hemojuvelin (HJV). As a negative regulator of hepcidin, matriptase‐2 is an attractive target for correcting iron overload. The Kunitz‐type inhibitors hepatocyte growth factor activator inhibitor 1 (HAI‐1) and 2 (HAI‐2) were charaterised as powerful inhibitors of matriptase‐2. Different assays were applied to determine the inhibition constants and to evaluate the downstream consequences in human liver cells; they demonstrated that HAI‐2, in particular, represents a scaffold for the design of potent matriptase‐2 inhibitors. The binding mode of the matriptase‐2‐HAI‐2 complex suggested by molecular modelling is illustrated. More information can be found in the full paper by M. Stirnberg et al. on page 595 in Issue 7, 2016 (DOI: 10.1002/cbic.201500651).