Interspecies Comparisons of the Effects of Potential Antiviral 3-Amidinophenylalanine Derivatives on Cytochrome P450 1A2 Isoenzyme
In vitro models of animals vulnerable to SARS-CoV-2 infection can support the characterization of effective antiviral drugs, such as synthetic inhibitors of the transmembrane protease serine 2 (TMPRSS2). Changes in cytochrome P450 (CYP) 1A2 activities in the presence of the potential TMPRSS2/matript...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-03-01
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| Series: | Veterinary Sciences |
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| Online Access: | https://www.mdpi.com/2306-7381/9/4/156 |
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| author | Zsófia Fedor Anna Szentkirályi-Tóth Gábor Nagy Zoltán Szimrók Eszter Varga Anna Pászti Zoltán Pászti Ákos Jerzsele Oliver Pilgram Torsten Steinmetzer Gábor Mátis Zsuzsanna Neogrády Erzsébet Pászti-Gere |
| author_facet | Zsófia Fedor Anna Szentkirályi-Tóth Gábor Nagy Zoltán Szimrók Eszter Varga Anna Pászti Zoltán Pászti Ákos Jerzsele Oliver Pilgram Torsten Steinmetzer Gábor Mátis Zsuzsanna Neogrády Erzsébet Pászti-Gere |
| author_sort | Zsófia Fedor |
| collection | DOAJ |
| description | In vitro models of animals vulnerable to SARS-CoV-2 infection can support the characterization of effective antiviral drugs, such as synthetic inhibitors of the transmembrane protease serine 2 (TMPRSS2). Changes in cytochrome P450 (CYP) 1A2 activities in the presence of the potential TMPRSS2/matriptase inhibitors (MI) were measured using fluorometric and luminescent assays. Furthermore, the cytotoxicity of these inhibitors was evaluated using the MTS method. In addition, 60 min-long microsomal stability assays were performed using an UPLC-MS/MS procedure to elucidate depletion rates of the inhibitors. CYP1A2 was influenced significantly by MI-463 and MI-1900 in rat microsomes, by MI-432 and MI-482 in beagle microsomes, and by MI-432, MI-463, MI-482, and MI-1900 in cynomolgus monkey microsomes. The IC50 values in monkey microsomes were 1.30 ± 0.14 µM, 2.4 ± 1.4 µM, 0.21 ± 0.09 µM, and 1.1 ± 0.8 µM for inhibitors MI-432, MI-463, MI-482, and MI-1900, respectively. The depletion rates of the parent compounds were lower than 50%, independently of the investigated animal species. The host cell factor TMPRSS2 is of key importance for the cross-species spread of SARS-CoV-2. Studies of the in vitro biotransformation of TMPRSS2 inhibitors provide additional information for the development of new antiviral drugs. |
| first_indexed | 2024-03-09T10:27:54Z |
| format | Article |
| id | doaj.art-2daa9330bc4048fdbcac8964c25dd57b |
| institution | Directory Open Access Journal |
| issn | 2306-7381 |
| language | English |
| last_indexed | 2024-03-09T10:27:54Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Veterinary Sciences |
| spelling | doaj.art-2daa9330bc4048fdbcac8964c25dd57b2023-12-01T21:31:24ZengMDPI AGVeterinary Sciences2306-73812022-03-019415610.3390/vetsci9040156Interspecies Comparisons of the Effects of Potential Antiviral 3-Amidinophenylalanine Derivatives on Cytochrome P450 1A2 IsoenzymeZsófia Fedor0Anna Szentkirályi-Tóth1Gábor Nagy2Zoltán Szimrók3Eszter Varga4Anna Pászti5Zoltán Pászti6Ákos Jerzsele7Oliver Pilgram8Torsten Steinmetzer9Gábor Mátis10Zsuzsanna Neogrády11Erzsébet Pászti-Gere12Department of Pharmacology and Toxicology, University of Veterinary Medicine, 1078 Budapest, HungaryDepartment of Pharmacology and Toxicology, University of Veterinary Medicine, 1078 Budapest, HungaryDepartment of Pharmacology and Toxicology, University of Veterinary Medicine, 1078 Budapest, HungaryDepartment of Pharmacology and Toxicology, University of Veterinary Medicine, 1078 Budapest, HungaryDepartment of Pharmacology and Toxicology, University of Veterinary Medicine, 1078 Budapest, HungaryDepartment of Pharmacology and Toxicology, University of Veterinary Medicine, 1078 Budapest, HungaryResearch Centre for Natural Sciences, Institute of Materials and Environmental Chemistry, 1117 Budapest, HungaryDepartment of Pharmacology and Toxicology, University of Veterinary Medicine, 1078 Budapest, HungaryFaculty of Pharmacy, Institute of Pharmaceutical Chemistry, Philipps University Marburg, 35037 Marburg, GermanyFaculty of Pharmacy, Institute of Pharmaceutical Chemistry, Philipps University Marburg, 35037 Marburg, GermanyDivision of Biochemistry, Department of Physiology and Biochemistry, University of Veterinary Medicine, 1078 Budapest, HungaryDivision of Biochemistry, Department of Physiology and Biochemistry, University of Veterinary Medicine, 1078 Budapest, HungaryDepartment of Pharmacology and Toxicology, University of Veterinary Medicine, 1078 Budapest, HungaryIn vitro models of animals vulnerable to SARS-CoV-2 infection can support the characterization of effective antiviral drugs, such as synthetic inhibitors of the transmembrane protease serine 2 (TMPRSS2). Changes in cytochrome P450 (CYP) 1A2 activities in the presence of the potential TMPRSS2/matriptase inhibitors (MI) were measured using fluorometric and luminescent assays. Furthermore, the cytotoxicity of these inhibitors was evaluated using the MTS method. In addition, 60 min-long microsomal stability assays were performed using an UPLC-MS/MS procedure to elucidate depletion rates of the inhibitors. CYP1A2 was influenced significantly by MI-463 and MI-1900 in rat microsomes, by MI-432 and MI-482 in beagle microsomes, and by MI-432, MI-463, MI-482, and MI-1900 in cynomolgus monkey microsomes. The IC50 values in monkey microsomes were 1.30 ± 0.14 µM, 2.4 ± 1.4 µM, 0.21 ± 0.09 µM, and 1.1 ± 0.8 µM for inhibitors MI-432, MI-463, MI-482, and MI-1900, respectively. The depletion rates of the parent compounds were lower than 50%, independently of the investigated animal species. The host cell factor TMPRSS2 is of key importance for the cross-species spread of SARS-CoV-2. Studies of the in vitro biotransformation of TMPRSS2 inhibitors provide additional information for the development of new antiviral drugs.https://www.mdpi.com/2306-7381/9/4/1563-amidinophenylalaninebeaglecynomolgus monkey microsomeSARS-CoV-2CYP1A2hepatocytes |
| spellingShingle | Zsófia Fedor Anna Szentkirályi-Tóth Gábor Nagy Zoltán Szimrók Eszter Varga Anna Pászti Zoltán Pászti Ákos Jerzsele Oliver Pilgram Torsten Steinmetzer Gábor Mátis Zsuzsanna Neogrády Erzsébet Pászti-Gere Interspecies Comparisons of the Effects of Potential Antiviral 3-Amidinophenylalanine Derivatives on Cytochrome P450 1A2 Isoenzyme Veterinary Sciences 3-amidinophenylalanine beagle cynomolgus monkey microsome SARS-CoV-2 CYP1A2 hepatocytes |
| title | Interspecies Comparisons of the Effects of Potential Antiviral 3-Amidinophenylalanine Derivatives on Cytochrome P450 1A2 Isoenzyme |
| title_full | Interspecies Comparisons of the Effects of Potential Antiviral 3-Amidinophenylalanine Derivatives on Cytochrome P450 1A2 Isoenzyme |
| title_fullStr | Interspecies Comparisons of the Effects of Potential Antiviral 3-Amidinophenylalanine Derivatives on Cytochrome P450 1A2 Isoenzyme |
| title_full_unstemmed | Interspecies Comparisons of the Effects of Potential Antiviral 3-Amidinophenylalanine Derivatives on Cytochrome P450 1A2 Isoenzyme |
| title_short | Interspecies Comparisons of the Effects of Potential Antiviral 3-Amidinophenylalanine Derivatives on Cytochrome P450 1A2 Isoenzyme |
| title_sort | interspecies comparisons of the effects of potential antiviral 3 amidinophenylalanine derivatives on cytochrome p450 1a2 isoenzyme |
| topic | 3-amidinophenylalanine beagle cynomolgus monkey microsome SARS-CoV-2 CYP1A2 hepatocytes |
| url | https://www.mdpi.com/2306-7381/9/4/156 |
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