Study of Potential Blocking Peptides Targeting the SARS-CoV-2 RBD/hACE2 Interaction

Area of Science:

• Virology
• Biotechnology
• Drug Discovery

Background:

• Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, necessitating new treatments due to emerging variants.
• The virus enters cells by the spike protein's receptor-binding domain (RBD) binding to human angiotensin-converting enzyme 2 (ACE2).
• Previous in silico studies identified peptides BP2, BP9, and BP11 as potential disruptors of the RBD-ACE2 interaction.

Purpose of the Study:

• To experimentally validate the efficacy of peptides BP2, BP9, and BP11 in inhibiting the SARS-CoV-2 RBD-ACE2 interaction.
• To assess the production yield and binding capabilities of these peptides against various RBD variants.
• To identify the most promising peptide for therapeutic development against SARS-CoV-2.

Main Methods:

• Recombinant production of peptides BP2, BP9, and BP11 in the yeast Komagataella phaffii.
• In vitro assessment of peptide activity using binding assays with multiple RBD variants.
• Evaluation of the inhibition of the RBD-ACE2 interaction and determination of IC50 values.

Main Results:

• Peptides BP2, BP9, and BP11 were successfully produced with yields of 14.34, 4.01, and 1.35 mg/L, respectively.
• All three peptides demonstrated interaction with RBD from SARS-CoV-2 variants of concern, with BP2 showing superior recognition.
• The peptides inhibited the RBD/hACE2 interaction with IC50 values ranging from 1.03 to 5.35 nM, BP2 being the most effective.

Conclusions:

• Peptide BP2 shows significant promise as a therapeutic candidate for developing novel interventions against SARS-CoV-2.
• The findings support the potential of BP2 and related peptides in targeting coronaviruses that utilize hACE2 for cell entry.
• Experimental validation confirms the in silico predictions, paving the way for further drug development efforts.