SMYD2 Inhibition Downregulates TMPRSS2 and Decreases SARS-CoV-2 Infection in Human Intestinal and Airway Epithelial Cells
Open Access
- 8 April 2022
- Vol. 11 (8), 1262
- https://doi.org/10.3390/cells11081262
Abstract
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.Funding Information
- Federal Ministry of Education and Research (BMBF SenseCoV2 01KI20172A)
- Deutsche Forschungsgemeinschaft (DFG Fokus COVID-19, EN 423/7-1, SFB1181 (C05), TRR241 (A03), individual grant BE3686/9)
- Bavarian State Ministry of Science and the Arts and Bavarian State Ministry of Health Bay-VOC (Bavarian State Ministry of Science and the Arts and Bavarian State Ministry of Health Bay-VOC)
This publication has 56 references indexed in Scilit:
- TMPRSS2 Activates the Human Coronavirus 229E for Cathepsin-Independent Host Cell Entry and Is Expressed in Viral Target Cells in the Respiratory EpitheliumJournal of Virology, 2013
- The Spike Protein of the Emerging Betacoronavirus EMC Uses a Novel Coronavirus Receptor for Entry, Can Be Activated by TMPRSS2, and Is Targeted by Neutralizing AntibodiesJournal of Virology, 2013
- Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMCNature, 2013
- Structural Basis of Substrate Methylation and Inhibition of SMYD2Structure, 2011
- Efficient Activation of the Severe Acute Respiratory Syndrome Coronavirus Spike Protein by the Transmembrane Protease TMPRSS2Journal of Virology, 2010
- A post-translational modification code for transcription factors: sorting through a sea of signalsTrends in Cell Biology, 2009
- The Tale of Two DomainsMolecular & Cellular Proteomics, 2008
- Proteolytic Activation of Influenza Viruses by Serine Proteases TMPRSS2 and HAT from Human Airway EpitheliumJournal of Virology, 2006
- Phenotypic Analysis of Mice Lacking the Tmprss2-Encoded ProteaseMolecular and Cellular Biology, 2006
- Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirusNature, 2003