Computational Design and Evaluation of Peptides to Target SARS-CoV-2 Spike-ACE2 Interaction

Area of Science:

• Biochemistry
• Virology
• Drug Discovery

Background:

• The SARS-CoV-2 spike protein's receptor-binding domain (RBD) mediates viral entry by binding to human ACE2.
• Targeting the RBD-ACE2 interaction is a key therapeutic strategy against SARS-CoV-2.
• Existing research explored antibodies, aptamers, and peptides for this purpose.

Purpose of the Study:

• To identify and develop a novel peptide inhibitor targeting the SARS-CoV-2 RBD-ACE2 interaction.
• To evaluate the efficacy of designed peptides in disrupting viral entry.

Main Methods:

• Utilized a large peptide database (PepI-Covid19) for structural design.
• Employed molecular dynamics simulations to screen peptides.
• Synthesized and validated top peptide candidates using in vitro and cell-based assays.

Main Results:

• One synthesized peptide, PEP10, demonstrated significant disruption of the RBD-ACE2 complex.
• PEP10 effectively inhibited cell entry mediated by SARS-CoV-2 spike proteins from D614G, Delta, and Omicron variants.
• PEP10 blocked the binding of two molecules, preventing viral infection.

Conclusions:

• PEP10 is a potent inhibitor of SARS-CoV-2 entry by disrupting the RBD-ACE2 interaction.
• This peptide shows broad efficacy against key SARS-CoV-2 variants.
• PEP10 serves as a potential scaffold for developing optimized antiviral therapeutics.