3-Amidinophenylalanine-Derived Matriptase Inhibitors can Modulate Hepcidin Production in vitro

Pászti-Gere, Erzsébet and Szombath, Gergely and Gütschow, Michael and Steinmetzer, Torsten and Székács, András (2020) 3-Amidinophenylalanine-Derived Matriptase Inhibitors can Modulate Hepcidin Production in vitro. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY, 393. pp. 511-520. ISSN 0028-1298 (print); 1432-1912 (online)

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Abstract

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 mu M. 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.

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