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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Bibliographic Details
Published in:Cells (Basel, Switzerland) Switzerland), 2022-04, Vol.11 (8), p.1262
Main Authors: Yu, Yu-Qiang, Herrmann, Alexandra, Thonn, Veronika, Cordsmeier, Arne, Neurath, Markus F, Ensser, Armin, Becker, Christoph
Format: Article
Language:English
Subjects:
Amino acids
Antibodies
Antiviral activity
Antiviral Agents - pharmacology
AZ505
BAY598
Cell culture
Cell cycle
Cloning
Coronaviruses
COVID-19
COVID-19 - pathology
Cytotoxicity
Drugs
Epithelial cells
Epithelial Cells - metabolism
Epithelial Cells - virology
Experiments
FDA approval
Gene expression
Genomes
Histone-Lysine N-Methyltransferase - genetics
Humans
Infections
Lysine
Methyltransferase
mRNA
Mutation
Proteins
Replication
SARS-CoV-2
SARS-CoV-2 - drug effects
Serine Endopeptidases - genetics
Severe acute respiratory syndrome coronavirus 2
SMYD2
Spike Glycoprotein, Coronavirus - metabolism
Spike protein
TMPRSS2
Viral infections
Virus Internalization
Viruses
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Summary: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.
ISSN:2073-4409
2073-4409
DOI:10.3390/cells11081262