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Structural basis of SARS-CoV-2 main protease inhibition by a broad-spectrum anti-coronaviral drug

Yu-Chuan Wang1, Wen-Hao Yang2, Chia-Shin Yang1

  • 1Institute of New Drug Development, China Medical University Taichung 40402, Taiwan.

American Journal of Cancer Research
|September 9, 2020
PubMed

Insights

GC376, an existing antiviral, effectively inhibits SARS-CoV-2 main protease (Mpro) activity. This drug repurposing shows promise for treating COVID-19, with GC376 demonstrating strong binding and inhibition.

Area of Science:

  • Virology
  • Drug Discovery
  • Biochemistry

Background:

  • The COVID-19 pandemic, caused by SARS-CoV-2, necessitates effective antiviral treatments.
  • The SARS-CoV-2 main protease (Mpro) is crucial for viral replication and a key therapeutic target.
  • GC376 is a known broad-spectrum Mpro inhibitor effective against other coronaviruses.

Purpose of the Study:

  • To evaluate the potential of repurposing the antiviral GC376 for treating COVID-19.
  • To determine the binding affinity and inhibitory activity of GC376 against SARS-CoV-2 Mpro.
  • To elucidate the structural basis of GC376 interaction with SARS-CoV-2 Mpro.

Main Methods:

  • Isothermal titration calorimetry (ITC) to measure binding affinity (KD).
  • Fluorescence resonance energy transfer (FRET) assay to determine IC50 values.
  • X-ray crystallography to determine the co-crystal structure of Mpro with GC376.

Main Results:

  • GC376 exhibits tight binding to SARS-CoV-2 Mpro (KD = 1.6 μM).
  • GC376 potently inhibits Mpro activity with an IC50 of 0.89 μM.
  • The crystal structure reveals GC376 forms a covalent bond with the catalytic Cys145 residue.

Conclusions:

  • GC376 is a potent inhibitor of SARS-CoV-2 Mpro.
  • Its established safety profile in animals makes it a promising candidate for COVID-19 treatment.
  • Repurposing GC376 offers a viable strategy for combating the COVID-19 pandemic.

Keywords:
COVID-19SARS-CoV-2coronavirus (CoV)drug actiondrug developmentdrug screeningprotease inhibitorstructural biology

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