1. In vitro interaction of potential antiviral TMPRSS2 inhibitors with human serum albumin and cytochrome P 450 isoenzymes.
- Author
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Pászti-Gere E, Szentkirályi A, Fedor Z, Nagy G, Szimrók Z, Pászti Z, Pászti A, Pilgram O, Steinmetzer T, Bodnárová S, Fliszár-Nyúl E, and Poór M
- Subjects
- Antiviral Agents analysis, Antiviral Agents pharmacology, Dose-Response Relationship, Drug, Humans, Isoenzymes metabolism, Microsomes, Liver drug effects, Microsomes, Liver metabolism, Protease Inhibitors analysis, Protease Inhibitors pharmacology, Protein Binding physiology, Serine Endopeptidases analysis, Spectrometry, Fluorescence methods, Tandem Mass Spectrometry methods, Antiviral Agents metabolism, Cytochrome P-450 Enzyme System metabolism, Protease Inhibitors metabolism, Serine Endopeptidases metabolism, Serum Albumin, Human metabolism
- Abstract
The interactions of four sulfonylated Phe(3-Am)-derived inhibitors (MI-432, MI-463, MI-482 and MI-1900) of type II transmembrane serine proteases (TTSP) such as transmembrane protease serine 2 (TMPRSS2) were examined with serum albumin and cytochrome P450 (CYP) isoenzymes. Complex formation with albumin was investigated using fluorescence spectroscopy. Furthermore, microsomal hepatic CYP1A2, 2C9, 2C19 and 3A4 activities in presence of these inhibitors were determined using fluorometric assays. The inhibitory effects of these compounds on human recombinant CYP3A4 enzyme were also examined. In addition, microsomal stability assays (60-min long) were performed using an UPLC-MS/MS method to determine depletion percentage values of each compound. The inhibitors showed no or only weak interactions with albumin, and did not inhibit CYP1A2, 2C9 and 2C19. However, the compounds tested proved to be potent inhibitors of CYP3A4 in both assays performed. Within one hour, 20%, 12%, 14% and 25% of inhibitors MI-432, MI-463, MI-482 and MI-1900, respectively, were degraded. As essential host cell factor for the replication of the pandemic SARS-CoV-2, the TTSP TMPRSS2 emerged as an important target in drug design. Our study provides further preclinical data on the characterization of this type of inhibitors for numerous trypsin-like serine proteases., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
- Published
- 2022
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