Author:
Gamba Dávid,van Eijk Nicholas,Lányi Katalin,Monostory Katalin,Steinmetzer Torsten,Marosi András,Rácz Anita,Bajusz Dávid,Kruhl Diana,Böttcher-Friebertshäuser Eva,Pászti-Gere Erzsébet
Abstract
AbstractCertain corona- and influenza viruses utilize type II transmembrane serine proteases for cell entry, making these enzymes potential drug targets for the treatment of viral respiratory infections. In this study, the cytotoxicity and inhibitory effects of seven matriptase/TMPRSS2 inhibitors (MI-21, MI-463, MI-472, MI-485, MI-1900, MI-1903, and MI-1904) on cytochrome P450 enzymes were evaluated using fluorometric assays. Additionally, their antiviral activity against influenza A virus subtypes H1N1 and H9N2 was assessed. The metabolic depletion rates of these inhibitors in human primary hepatocytes were determined over a 120-min period by LC–MS/MS, and PK parameters were calculated. The tested compounds, with the exception of MI-21, displayed potent inhibition of CYP3A4, while all compounds lacked inhibitory effects on CYP1A2, CYP2C9, CYP2C19, and CYP2D6. The differences between the CYP3A4 activity within the series were rationalized by ligand docking. Elucidation of PK parameters showed that inhibitors MI-463, MI-472, MI-485, MI-1900 and MI-1904 were more stable compounds than MI-21 and MI-1903. Anti-H1N1 properties of inhibitors MI-463 and MI-1900 and anti-H9N2 effects of MI-463 were shown at 20 and 50 µM after 24 h incubation with the inhibitors, suggesting that these inhibitors can be applied to block entry of these viruses by suppressing host matriptase/TMPRSS2-mediated cleavage.
Funder
Hungarian Academy of Sciences: János Bolyai Research Scholarship
New National Excellence Program of the Ministry for Culture and Innovation from the source of the National Research, Development, and Innovation Fund
National Research Development and Innovation Office of Hungary
University of Veterinary Medicine Budapest
University of Veterinary Medicine
Publisher
Springer Science and Business Media LLC
Cited by
1 articles.
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