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TMPRSS2 isoform 1 downregulation by G-quadruplex stabilization induces SARS-CoV-2 replication arrest
Alessio De Magis1,2, Philipp Schult3,4, Antonia Schönleber3
1Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, Germany. demagis.alessio@hsr.it.
BMC Biology
|January 7, 2024
Summary
G-quadruplex stabilization targets TMPRSS2 isoform 1, impacting SARS-CoV-2 replication. This reveals a new mechanism where TMPRSS2 gene expression changes influence severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection outcomes.
Area of Science:
- Virology
- Molecular Biology
- Genetics
Background:
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection relies on host factors like angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2).
- Inhibitors targeting ACE2 or TMPRSS2 are potential therapeutic strategies against SARS-CoV-2.
- Modulating TMPRSS2 activity could influence SARS-CoV-2 infection outcomes.
Purpose of the Study:
- To investigate the role of TMPRSS2 beyond viral entry, specifically in viral replication.
- To explore the impact of G-quadruplex (G4) stabilization on TMPRSS2 gene expression and SARS-CoV-2 replication.
- To identify specific G4 structures within TMPRSS2 and their interaction with G4 ligands.
Main Methods:
- Downregulation of distinct TMPRSS2 isoforms to assess their roles in viral replication.
- Chemical compound treatment to stabilize G-quadruplex structures and observe effects on TMPRSS2 gene expression.
- Analysis of single nucleotide polymorphisms (SNPs) within G4 motifs of TMPRSS2.
Main Results:
- TMPRSS2 isoform 1 was identified as crucial for SARS-CoV-2 replication, in addition to its role in viral entry.
- G-quadruplex stabilization by chemical compounds was shown to affect TMPRSS2 gene expression.
- A specific G4 in TMPRSS2 isoform 1's first exon was targeted by a G4 ligand, impacting viral replication.
- A reported SNP in this G4 motif disrupted the G4 structure, rendering TMPRSS2 unresponsive to G4 ligand treatment.
Conclusions:
- G4 stabilization represents a novel mechanism influencing SARS-CoV-2 replication through modulation of TMPRSS2 isoform 1 gene expression.
- Targeting specific G4 structures in TMPRSS2 offers a potential therapeutic avenue for controlling SARS-CoV-2.
- Understanding the interplay between G4s, TMPRSS2 isoforms, and viral replication is key to developing effective antiviral strategies.
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