Structure-based design of a SARS-CoV-2 Omicron-specific inhibitor

Area of Science:

• Virology
• Structural Biology
• Drug Discovery

Background:

• The Omicron variant of SARS-CoV-2 possesses numerous mutations, including three in the HR1 region of the spike glycoprotein.
• These mutations impact the membrane fusion activity, a critical step in viral entry.
• The N969K mutation specifically alters the HR1HR2 postfusion bundle structure, reducing the efficacy of existing fusion inhibitors.

Purpose of the Study:

• To design and characterize an Omicron-specific peptide inhibitor targeting the SARS-CoV-2 spike protein.
• To investigate the structural impact of the N969K mutation on the HR1HR2 postfusion bundle.
• To restore the inhibitory activity of fusion-entry peptide inhibitors against the Omicron variant.

Main Methods:

• Structural analysis of the Omicron HR1HR2 postfusion bundle.
• Design of a modified peptide inhibitor incorporating an additional residue in HR2.
• Evaluation of inhibitor efficacy using cell-cell fusion and VSV-SARS-CoV-2 chimera infection assays.

Main Results:

• The N969K mutation causes significant structural distortion in the HR1HR2 postfusion bundle.
• The designed Omicron-specific inhibitor accommodates the N969K mutation, relieving structural distortion.
• The new inhibitor fully recovered the inhibition activity lost by the original peptide against the Omicron variant.

Conclusions:

• A novel peptide inhibitor strategy can overcome Omicron-specific mutations in SARS-CoV-2.
• This approach may be applicable for developing inhibitors against future SARS-CoV-2 variants.
• HR2 region interactions are crucial for the initial steps of HR1 binding during S protein fusion.