Omicron Spike Protein is Vulnerable to Reduction.

Area of Science:

• Virology
• Structural Biology
• Biochemistry

Background:

• The SARS-CoV-2 spike (S) protein mediates host cell entry by binding to the ACE2 receptor.
• Disulfide bonds within the S protein structure present potential targets for reductive cleavage.

Purpose of the Study:

• To investigate the impact of chemical reduction on SARS-CoV-2 spike proteins from various variants.
• To identify specific mutations contributing to altered reduction susceptibility in Omicron variants.

Main Methods:

• Utilized a tri-part split luciferase-based binding assay to assess S protein binding activity.
• Analyzed the effects of chemical reduction on spike proteins from different SARS-CoV-2 variants, including Omicron.
• Manipulated Omicron-specific mutations to determine their role in reduction vulnerability.

Main Results:

• Omicron-lineage spike proteins exhibited significant vulnerability to chemical reduction compared to other variants.
• Mutations within the receptor binding module (RBM) of Omicron were identified as key determinants of this vulnerability.
• Specific disulfide bonds (C480-C488 and C379-C432) were found to be susceptible to cleavage in Omicron, impairing binding and stability.

Conclusions:

• The heightened susceptibility of Omicron S proteins to reduction provides a potential therapeutic avenue.
• Targeting these specific disulfide bonds could lead to novel treatments for SARS-CoV-2 infections, particularly those caused by Omicron variants.