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

• DOI: 10.1007/s00210-019-01743-x
• Publication Date: 2019-10-28T23:03:25Z
• Authors: Erzsébet Pászti-Gere; Gergely Szombath; Michael Gütschow; Torsten Steinmetzer; András Székács
• Keywords: Male; 0301 basic medicine; RS Pharmacy and materia medica / gyógyszerészet; Dose-Response Relationship, Drug; Kupffer Cells; Swine; Phenylalanine; Serine Endopeptidases; Coculture Techniques; 3. Good health; 03 medical and health sciences; Hepcidins; gyógyászati eszközök; Hepatocytes; Animals; Original Article; Enzyme Inhibitors

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