Chemical Proteomics Approaches for Screening Small Molecule Inhibitors Covalently Binding to SARS-Cov-2

Area of Science:

• Drug discovery and development
• Virology
• Computational biology

Background:

• The rapid spread and evolution of SARS-CoV-2, particularly Omicron variants, necessitate novel therapeutic strategies.
• Current monoclonal antibody treatments are less effective against emerging SARS-CoV-2 variants, creating an urgent need for new antivirals.
• Developing broad-spectrum therapeutics is crucial to combat current and future SARS-CoV-2 strains and recombinants.

Purpose of the Study:

• To rapidly identify small molecule drugs capable of covalently binding to the SARS-CoV-2 Omicron variant's receptor binding domain (RBD).
• To establish and validate a comprehensive platform integrating artificial intelligence (AI), activity-based protein profiling (ABPP), and biochemical assays for accelerated drug discovery.
• To evaluate the neutralization potency of identified drug candidates against Omicron variants.

Main Methods:

• Combined application of artificial intelligence (AI) and activity-based protein profiling (ABPP) for high-throughput screening of small molecules.
• Surface plasmon resonance (SPR) assays to confirm binding kinetics and affinity of small molecules to the RBD.
• Pseudo-virus neutralization experiments to assess the antiviral efficacy of drug candidates.
• Molecular docking simulations to predict binding interactions.

Main Results:

• AI and ABPP successfully identified small molecules with the potential to covalently bind to the Omicron RBD.
• Gallic acid, an FDA-approved drug, exhibited significant neutralization potency against Omicron pseudo-virus, with an IC50 of 23.56 × 10⁻⁶ m.
• The integrated platform demonstrated effectiveness in rapidly identifying and evaluating potential anti-SARS-CoV-2 small molecule drugs.

Conclusions:

• A novel platform combining AI, biochemical assays, SPR, molecular docking, and pseudo-virus screening enables rapid identification and validation of anti-SARS-CoV-2 small molecule drugs.
• Gallic acid represents a promising therapeutic candidate with potent neutralization activity against Omicron variants.
• This approach provides a validated strategy for discovering therapeutics against current and emerging SARS-CoV-2 variants.