Plausible blockers of Spike RBD in SARS-CoV2-molecular design and underlying interaction dynamics from high-level...

Area of Science:

• Biochemistry
• Structural Biology
• Drug Discovery

Background:

• COVID-19, caused by SARS-CoV-2, exhibits rapid transmission.
• The Spike protein's Receptor Binding Domain (RBD_Spike) binds to human ACE2, initiating infection.
• Blocking the RBD_Spike-ACE2 interaction is a potential therapeutic strategy.

Purpose of the Study:

• To design non-virulent protein mimics of RBD_Spike.
• To create competitive inhibitors that block ACE2 binding.
• To explore rational protein design for therapeutic applications.

Main Methods:

• Protein design approach using structural analyses of homologous complexes.
• Homology-based threading and strategic "hydrophobic ↔ polar" mutations.
• Free energy estimates to validate binding affinity of designed mimics.

Main Results:

• Designed protein mimics show signatures of stable, high-affinity binding to ACE2.
• Mimics effectively override the native quasi-stable RBD_Spike-ACE2 interaction.
• Demonstrated the potential of adapting natural protein structures in rational design.

Conclusions:

• Rational protein design using homology and targeted mutations can create effective therapeutic agents.
• Developed protein mimics offer a promising strategy to inhibit SARS-CoV-2 entry.
• This approach provides a breakthrough for designing novel antiviral therapies.