SMYD2 Inhibition Downregulates TMPRSS2 and Decreases SARS-CoV-2 Infection in Human Intestinal and Airway Epithelial Cells
The COVID-19 pandemic caused by SARS-CoV-2 has lasted for more than two years. Despite the presence of very effective vaccines, the number of virus variants that escape neutralizing antibodies is growing. Thus, there is still a need for effective antiviral treatments that target virus replication in...
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MDPI AG
2022-04-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/11/8/1262 |
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| author | Yu-Qiang Yu Alexandra Herrmann Veronika Thonn Arne Cordsmeier Markus F. Neurath Armin Ensser Christoph Becker |
| author_facet | Yu-Qiang Yu Alexandra Herrmann Veronika Thonn Arne Cordsmeier Markus F. Neurath Armin Ensser Christoph Becker |
| author_sort | Yu-Qiang Yu |
| collection | DOAJ |
| description | The COVID-19 pandemic caused by SARS-CoV-2 has lasted for more than two years. Despite the presence of very effective vaccines, the number of virus variants that escape neutralizing antibodies is growing. Thus, there is still a need for effective antiviral treatments that target virus replication independently of the circulating variant. Here, we show for the first time that deficiency or pharmacological inhibition of the cellular lysine-methyltransferase SMYD2 decreases TMPRSS2 expression on both mRNA and protein levels. SARS-CoV-2 uses TMPRSS2 for priming its spike protein to infect target cells. Treatment of cultured cells with the SMYD2 inhibitors AZ505 or BAY598 significantly inhibited viral replication. In contrast, treatment of Vero E6 cells, which do not express detectable amounts of TMPRSS2, had no effect on SARS-CoV-2 infection. Moreover, by generating a recombinant reporter virus that expresses the spike protein of the Delta variant of SARS-CoV-2, we demonstrate that BAY598 exhibits similar antiviral activity against this variant of concern. In summary, SMYD2 inhibition downregulates TMPRSS2 and blocks viral replication. Targeting cellular SMYD2 represents a promising tool to curtail SARS-CoV-2 infection. |
| first_indexed | 2024-03-09T11:02:25Z |
| format | Article |
| id | doaj.art-a07780d85098459795004c74f1c37f67 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T11:02:25Z |
| publishDate | 2022-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-a07780d85098459795004c74f1c37f672023-12-01T01:12:49ZengMDPI AGCells2073-44092022-04-01118126210.3390/cells11081262SMYD2 Inhibition Downregulates TMPRSS2 and Decreases SARS-CoV-2 Infection in Human Intestinal and Airway Epithelial CellsYu-Qiang Yu0Alexandra Herrmann1Veronika Thonn2Arne Cordsmeier3Markus F. Neurath4Armin Ensser5Christoph Becker6Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91052 Erlangen, GermanyInstitute of Clinical and Molecular Virology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91052 Erlangen, GermanyDepartment of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91052 Erlangen, GermanyInstitute of Clinical and Molecular Virology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91052 Erlangen, GermanyDepartment of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91052 Erlangen, GermanyInstitute of Clinical and Molecular Virology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91052 Erlangen, GermanyDepartment of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91052 Erlangen, GermanyThe COVID-19 pandemic caused by SARS-CoV-2 has lasted for more than two years. Despite the presence of very effective vaccines, the number of virus variants that escape neutralizing antibodies is growing. Thus, there is still a need for effective antiviral treatments that target virus replication independently of the circulating variant. Here, we show for the first time that deficiency or pharmacological inhibition of the cellular lysine-methyltransferase SMYD2 decreases TMPRSS2 expression on both mRNA and protein levels. SARS-CoV-2 uses TMPRSS2 for priming its spike protein to infect target cells. Treatment of cultured cells with the SMYD2 inhibitors AZ505 or BAY598 significantly inhibited viral replication. In contrast, treatment of Vero E6 cells, which do not express detectable amounts of TMPRSS2, had no effect on SARS-CoV-2 infection. Moreover, by generating a recombinant reporter virus that expresses the spike protein of the Delta variant of SARS-CoV-2, we demonstrate that BAY598 exhibits similar antiviral activity against this variant of concern. In summary, SMYD2 inhibition downregulates TMPRSS2 and blocks viral replication. Targeting cellular SMYD2 represents a promising tool to curtail SARS-CoV-2 infection.https://www.mdpi.com/2073-4409/11/8/1262SMYD2TMPRSS2SARS-CoV-2COVID-19BAY598AZ505 |
| spellingShingle | Yu-Qiang Yu Alexandra Herrmann Veronika Thonn Arne Cordsmeier Markus F. Neurath Armin Ensser Christoph Becker SMYD2 Inhibition Downregulates TMPRSS2 and Decreases SARS-CoV-2 Infection in Human Intestinal and Airway Epithelial Cells Cells SMYD2 TMPRSS2 SARS-CoV-2 COVID-19 BAY598 AZ505 |
| title | SMYD2 Inhibition Downregulates TMPRSS2 and Decreases SARS-CoV-2 Infection in Human Intestinal and Airway Epithelial Cells |
| title_full | SMYD2 Inhibition Downregulates TMPRSS2 and Decreases SARS-CoV-2 Infection in Human Intestinal and Airway Epithelial Cells |
| title_fullStr | SMYD2 Inhibition Downregulates TMPRSS2 and Decreases SARS-CoV-2 Infection in Human Intestinal and Airway Epithelial Cells |
| title_full_unstemmed | SMYD2 Inhibition Downregulates TMPRSS2 and Decreases SARS-CoV-2 Infection in Human Intestinal and Airway Epithelial Cells |
| title_short | SMYD2 Inhibition Downregulates TMPRSS2 and Decreases SARS-CoV-2 Infection in Human Intestinal and Airway Epithelial Cells |
| title_sort | smyd2 inhibition downregulates tmprss2 and decreases sars cov 2 infection in human intestinal and airway epithelial cells |
| topic | SMYD2 TMPRSS2 SARS-CoV-2 COVID-19 BAY598 AZ505 |
| url | https://www.mdpi.com/2073-4409/11/8/1262 |
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