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Multi-target Parallel Processing Approach for Gene-to-structure Determination of the Influenza Polymerase PB2 Subunit
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Novel Coronavirus Polymerase and Nucleotidyl-Transferase Structures: Potential to Target New Outbreaks

Wen-Fa Zhang1, Preyesh Stephen1,2, Jean-François Thériault1

  • 1Axe Molecular Endocrinology and Nephrology, CHU Research Center and Laval University, Québec City, Québec G1 V 4G2, Canada.

The Journal of Physical Chemistry Letters
|May 12, 2020
PubMed

Insights

Understanding SARS-CoV-2 RNA-dependent-RNA-polymerase (RdRp) is crucial for combating the pandemic. This study models SARS-CoV-2 RdRp and shows how inhibitors like Galidesivir bind, aiding drug development.

Area of Science:

  • Virology
  • Structural Biology
  • Drug Discovery

Background:

  • Coronaviruses (CoVs), including SARS-CoV-2, pose a continuous global health threat due to their high contagiousness.
  • RNA-dependent-RNA-polymerase (RdRp) is essential for viral replication, making it a key target for antiviral therapies.
  • SARS-CoV-2 RdRp and NiRAN show high sequence identity (98.1% and 93.2%) with SARS-CoV, suggesting conserved structural and functional properties.

Purpose of the Study:

  • To generate a 3D structural model of SARS-CoV-2 RdRp, NiRAN, nsp7, and nsp8.
  • To investigate the binding interactions of known RdRp inhibitors (Galidesivir, Favipiravir, Penciclovir) with the SARS-CoV-2 RdRp.
  • To provide insights for structure-based optimization of antiviral drugs against SARS-CoV-2.

Main Methods:

  • Comparative sequence alignment of RdRp and Spike proteins across six coronaviruses.
  • 3D structural modeling of SARS-CoV-2 RdRp, NiRAN, nsp7, and nsp8 based on SARS-CoV structures.
  • Molecular docking simulations to analyze the binding poses and interactions of three antiviral inhibitors.

Main Results:

  • High sequence identity observed between SARS-CoV-2 and SARS-CoV RdRp (98.1%) and NiRAN (93.2%).
  • A 3D structural model of key SARS-CoV-2 replication proteins was successfully generated.
  • Binding poses of Galidesivir, Favipiravir, and Penciclovir were elucidated, demonstrating their potential to inhibit viral RNA replication.

Conclusions:

  • The structural model and inhibitor binding analysis provide a foundation for developing effective SARS-CoV-2 antiviral strategies.
  • The conserved nature of RdRp across coronaviruses highlights its potential as a broad-spectrum antiviral target.
  • Structure-based drug design can be effectively employed to optimize existing inhibitors and discover new ones for SARS-CoV-2.

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