3-Amidinophenylalanine-derived matriptase inhibitors can modulate hepcidin production in vitro

Naunyn Schmiedebergs Arch Pharmacol. 2020 Mar;393(3):511-520. doi: 10.1007/s00210-019-01743-x. Epub 2019 Oct 28.


Matriptase-2 (MT-2) is a type II transmembrane serine protease and predominantly attached to the surface of hepatocytes. MT-2 decreases the production of hepcidin, a key regulator of iron homeostasis. In this study, the effects of four 3-amidinophenylalanine-derived combined matriptase-1/matriptase-2 (MT-1/2) inhibitors (MI-432, MI-441, MI-460, and MI-461) on hepcidin production were investigated in hepatocyte mono- and hepatocyte-Kupffer cell co-cultures. In MI-461-treated cell cultures, the extracellular hydrogen peroxide contents and the interleukin-6 and -8 (IL-6 and IL-8) levels were determined and compared to controls. Hepcidin overproduction was observed in hepatocytes upon treatment with MI-432, MI-441 and MI-461 at 50 μM. In contrast, extracellular hydrogen peroxide levels were not elevated significantly after matriptase inhibition with MI-461. Furthermore, MI-461 did not induce increases in IL-6 and IL-8 levels in these hepatic models. A model of the binding mode of inhibitor MI-461 in complex with MT-2 revealed numerous polar contacts contributing to the nanomolar potency of this compound. Based on the in vitro data on hepcidin regulation, treatment with MI-461 might be valuable in pathological states of iron metabolism without causing excessive oxidative stress.

Keywords: Extracellular ROS; Hepatocytes; Hepcidin; Hydrogel matrix; Matriptase inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Coculture Techniques
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Hepcidins / agonists*
  • Hepcidins / biosynthesis*
  • Kupffer Cells / drug effects
  • Kupffer Cells / metabolism
  • Male
  • Phenylalanine / analogs & derivatives
  • Phenylalanine / pharmacology*
  • Serine Endopeptidases / metabolism*
  • Swine


  • Enzyme Inhibitors
  • Hepcidins
  • Phenylalanine
  • Serine Endopeptidases
  • matriptase