ACE2- and HR2-Mimetic Peptides Inhibit Replication of Two SARS-CoV-2 Variants

Area of Science:

• Virology
• Drug Discovery
• Biochemistry

Background:

• Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) therapeutic strategies often target viral entry mechanisms.
• Inhibiting viral entry can be achieved by blocking the interaction between the spike protein's receptor-binding domain (RBD) and human angiotensin-converting enzyme 2 (ACE2), or by preventing viral-cellular membrane fusion.

Purpose of the Study:

• To design and evaluate mimetic peptides based on ACE2 and the SARS-CoV-2 spike protein stem.
• To identify peptides with high binding affinity and significant inhibitory activity against SARS-CoV-2 variants.

Main Methods:

• In silico molecular docking was employed to select peptides with optimal binding energy.
• Surrogate ELISA assays were used to assess the inhibition of the RBD-ACE2 interaction.
• In vitro assays using VeroE6 cells were conducted to determine the 50% inhibitory concentration (IC50) against SARS-CoV-2 Wuhan and Omicron variants.

Main Results:

• Peptides P-Nat and P-3 demonstrated significant inhibition of the RBD-ACE2 interaction (54% and 58.77%, respectively).
• P-Nat and P-3 exhibited potent inhibitory activity against both SARS-CoV-2 Wuhan and Omicron variants, with low IC50 values.
• The stem mimetic peptide P-K2 showed inhibitory activity specifically against the Omicron variant.

Conclusions:

• Peptides P-Nat and P-3 are promising candidates for inhibiting both Wuhan and Omicron SARS-CoV-2 variants.
• Peptide P-K2 demonstrates inhibitory potential against the Omicron variant.
• These designed peptides could serve as prophylactic agents by blocking viral entry into host cells.