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Nucleoside Analogs That Inhibit SARS-CoV-2 Replication by Blocking Interaction of Virus Polymerase with RNA

Elena Matyugina1, Ivan Petushkov2, Sergei Surzhikov1

  • 1Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia.

International Journal of Molecular Sciences
|February 25, 2023
PubMed

Insights

Researchers developed new nucleoside analogs to combat SARS-CoV-2. Some compounds inhibit viral RNA polymerase and replication, with potential for treating COVID-19 and influenza.

Area of Science:

  • Virology
  • Medicinal Chemistry
  • Drug Discovery

Background:

  • The COVID-19 pandemic caused by SARS-CoV-2 remains a global health crisis.
  • Developing effective antiviral drugs for SARS-CoV-2 is a critical unmet need.
  • Nucleoside analogs are a promising class of antiviral agents.

Purpose of the Study:

  • To design and synthesize novel nucleoside analogs.
  • To evaluate their antiviral activity against SARS-CoV-2 in vitro.
  • To investigate their mechanism of action, including RNA-dependent RNA polymerase inhibition.

Main Methods:

  • Drug repurposing strategy and screening of nucleoside analogs.
  • Synthesis of novel analogs based on lead compounds.
  • Cytotoxicity assays and antiviral activity evaluation in cell cultures.
  • Inhibition assays targeting SARS-CoV-2 RNA-dependent RNA polymerase.

Main Results:

  • Identified lead compounds inhibiting SARS-CoV-2 replication with EC50 values of 20-50 µM.
  • Synthesized and tested various analogs for cytotoxicity and antiviral efficacy.
  • Several compounds demonstrated inhibition of SARS-CoV-2 RNA-dependent RNA polymerase.
  • Three synthesized compounds also exhibited activity against influenza virus.

Conclusions:

  • Novel nucleoside analogs show promise as antiviral agents against SARS-CoV-2.
  • Inhibition of viral RNA-dependent RNA polymerase is a likely mechanism of action.
  • These compounds represent valuable scaffolds for further optimization into clinical antiviral drugs.
  • Potential for broad-spectrum antiviral activity, including influenza.
Keywords:
6-substituted derivatives of 3H-pyrrolo [2,3-d]-pyrimidine-2-oneSARS-CoV-2 RNA-dependent RNA polymeraseantiviral activitycarbocyclic and acyclic analogs of nucleosidesinfluenza virusinhibitors

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