Corilagin inhibits SARS-CoV-2 replication by targeting viral RNA-dependent RNA polymerase

Area of Science:

• Virology
• Medicinal Chemistry
• Drug Discovery

Background:

• Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) poses a significant global health threat.
• The RNA-dependent RNA polymerase (RdRp) is a critical target for antiviral development against SARS-CoV-2.
• Nucleoside analog inhibitors face challenges due to the proofreading activity of coronavirus RdRp.

Purpose of the Study:

• To identify and characterize non-nucleoside inhibitors of SARS-CoV-2 RdRp.
• To evaluate the antiviral efficacy and mechanism of action of corilagin (RAI-S-37).
• To assess the potential of corilagin as a SARS-CoV-2 therapeutic agent.

Main Methods:

• In vitro enzymatic assays to assess RdRp inhibition.
• Cell-based assays to evaluate antiviral activity.
• Computational modeling to predict binding interactions.
• Combination studies with existing antivirals.

Main Results:

• Corilagin (RAI-S-37) directly binds to SARS-CoV-2 RdRp and inhibits its polymerase activity.
• RAI-S-37 is effective in both cell-free and cell-based assays, resisting proofreading activity.
• Potent inhibition of SARS-CoV-2 infection with a low EC50 value (0.13 μmol/L).
• Computational modeling indicates RAI-S-37 binds to the palm domain, hindering nucleotide incorporation.
• Combination of RAI-S-37 with remdesivir shows additive antiviral activity.

Conclusions:

• Corilagin (RAI-S-37) is a promising non-nucleoside inhibitor of SARS-CoV-2 RdRp.
• Its unique mechanism and resistance to proofreading offer advantages over nucleoside analogs.
• Corilagin demonstrates significant potential for development into a much-needed therapeutic for SARS-CoV-2 infections, supported by existing safety and pharmacokinetic data.