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A Novel Y-Shaped, S-O-N-O-S-Bridged Cross-Link between Three Residues C22, C44, and K61 Is Frequently Observed in the

Kai S Yang, Lauren R Blankenship, Syuan-Ting Alex Kuo

  • 1Department of Biochemistry, Brandeis University, Waltham, Massachusetts 02453, United States.

ACS Chemical Biology
|January 11, 2023
PubMed

Insights

A novel cross-link in SARS-CoV-2 main protease (MPro) acts as a redox switch, opening the active site. This discovery offers new strategies for developing COVID-19 antivirals, potentially enhancing existing treatments.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Virology

Background:

  • Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) utilizes its main protease (MPro) for replication and pathogenesis.
  • MPro is a validated drug target for COVID-19 therapeutics.

Purpose of the Study:

  • To investigate novel post-translational modifications of SARS-CoV-2 MPro.
  • To explore the structural and functional implications of observed MPro cross-links.

Main Methods:

  • Crystallographic analysis of MPro crystals exposed to ambient conditions.
  • Structural determination of a novel Y-shaped, S-O-N-O-S-bridged cross-link involving C22, C44, and K61 residues.

Main Results:

  • A unique Y-shaped post-translational cross-link was frequently observed in MPro.
  • This cross-link connects Cys22, Cys44, and Lys61 residues via their side chains.
  • Formation of the cross-link results in a more open MPro active site, suggesting a redox-switch mechanism.

Conclusions:

  • The novel MPro cross-link may function as a redox switch, regulating protease activity.
  • The altered active site conformation presents a new target for antiviral drug development.
  • Small molecules stabilizing the cross-linked MPro could synergize with existing antivirals like Paxlovid to inhibit SARS-CoV-2 replication.

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