Suramin inhibits SARS-CoV-2 nucleocapsid phosphoprotein genome packaging function

Area of Science:

• Virology
• Drug Discovery
• Molecular Biology

Background:

• The COVID-19 pandemic persists due to SARS-CoV-2 variants, necessitating new antiviral drugs.
• The SARS-CoV-2 nucleocapsid (N) protein is crucial for viral packaging and immune evasion.
• Targeting novel SARS-CoV-2 proteins is a priority for developing effective COVID-19 therapeutics.

Purpose of the Study:

• To investigate Suramin as a potential antiviral agent against SARS-CoV-2.
• To identify therapeutic targets within the SARS-CoV-2 proteome.
• To understand the mechanism by which Suramin inhibits SARS-CoV-2 replication.

Main Methods:

• Miniaturized differential scanning fluorimetry and microscale thermophoresis to assess Suramin-N protein interactions.
• Molecular docking to predict Suramin binding sites.
• Electron microscopy to observe the effect of Suramin on RNP complex formation.
• Cell-based assays to evaluate Suramin's antiviral activity and effect on IFN-I production.

Main Results:

• Suramin binds to the N-terminal domain (NTD) and C-terminal domain (CTD) of the SARS-CoV-2 N protein with low-micromolar affinity.
• Suramin inhibits the RNA-binding function of the N protein and prevents RNP complex formation in vitro.
• Suramin reduces viral cytopathic effects in cell cultures and partially restores IFN-I production.
• Molecular docking identified potential druggable RNA-binding sites on the N protein.

Conclusions:

• Suramin effectively inhibits SARS-CoV-2 replication by disrupting viral genome packaging.
• The drug Suramin serves as a promising lead compound for designing novel COVID-19 antivirals.
• Targeting the SARS-CoV-2 N protein offers a viable strategy for combating current and future viral threats.