En Route to New Therapeutic Options for Iron Overload Diseases: Matriptase-2 as a Target for Kunitz-Type Inhibitors.
2016
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 factoractivator inhibitor 1 (
HAI-1) and
HAI-2 as powerful, slow-binding
matriptase-2 inhibitors. The binding modes of the
matriptase-2-
HAIcomplexes 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 livercells, 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.
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