In vitro interaction of potential antiviral TMPRSS2 inhibitors with human serum albumin and cytochrome P 450 isoenzymes - 16/01/22
, Anna Szentkirályi a, Zsófia Fedor a, Gábor Nagy a, Zoltán Szimrók a, Zoltán Pászti b, Anna Pászti a, Oliver Pilgram c, Torsten Steinmetzer c, Slávka Bodnárová d, e, Eszter Fliszár-Nyúl d, e, Miklós Poór d, e, ⁎ Bienvenue sur EM-consulte, la référence des professionnels de santé.
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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.
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Highlights |
• | TMPRSS2 inhibition is crucial for the antiviral effects of Phe(3-Am) compounds. |
• | The applied Phe(3-Am)-derived substances are potent inhibitors of CYP3A4. |
• | Phe(3-Am)-type inhibitors bind to albumin with low affinity. |
• | Phe(3-Am) derivatives did not inhibit CYP1A2, CYP2C9, and CYP2C19. |
• | Depletion rates of these compounds remained below 30% in human microsomes. |
Keywords : 3-amidinophenylalanine, Trypsin-like serine proteases, TMPRSS2, SARS-CoV-2, human serum albumin, Cytochrome P450 enzymes
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Vol 146
Article 112513- février 2022 Retour au numéro
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