Potential Self-Peptide Inhibitors of the SARS-CoV-2 Main Protease

Area of Science:

• Virology
• Structural Biology
• Drug Discovery

Background:

• The SARS-CoV-2 main protease (Mpro) is crucial for viral replication and a key drug target.
• Mpro comprises a catalytic domain and an alpha-helical domain (MproC).
• Self-peptides can influence protein folding and function, with SARS-CoV-1 MproC known to regulate Mpro.

Purpose of the Study:

• To investigate if SARS-CoV-2 MproC-derived self-peptides can modulate SARS-CoV-2 Mpro folding and function.
• To explore the potential of these self-peptides as inhibitors of Mpro.

Main Methods:

• Utilized coarse-grained structure-based models and molecular dynamics simulations.
• Studied the folding of MproC in the presence of various self-peptides.
• Analyzed the ability of self-peptides to replace native sequences within MproC.

Main Results:

• Two self-peptides, alpha1-helix and loop4, were found to substitute native sequences in MproC simulations.
• Prefolded self-peptides demonstrated a higher propensity to replace native sequences compared to unstructured ones.
• The alpha1-helix self-peptide exhibited kinetic stability, with limited exchange after insertion, unlike the loop4 peptide.

Conclusions:

• A prefolded alpha1-derived peptide has the potential to inhibit SARS-CoV-2 Mpro function.
• Self-peptide structure and kinetic stability are critical factors for designing effective Mpro inhibitors.
• This study provides principles for the rational design of self-peptide inhibitors targeting viral proteases.