ACE2- and HR2-Mimetic Peptides P-Nat, P-3, P-K2 Inhibit SARS-CoV-2 Variants by Blocking Entry
Background
The ongoing emergence of new SARS-CoV-2 variants, such as Omicron, and the persistent threat of future coronavirus pandemics underscore the critical need for broad-spectrum antiviral strategies. Current vaccines and antiviral therapies, while effective, often face limitations in preventing initial viral entry into host cells and in maintaining efficacy against rapidly evolving variants. A key therapeutic gap exists in developing agents that can effectively block the virus's primary entry mechanisms: the interaction between the viral spike protein's receptor-binding domain (RBD) and human angiotensin-converting enzyme 2 (ACE2), and subsequent viral-cellular membrane fusion.
Study Design
Researchers designed novel mimetic peptides based on human ACE2 and the HR2 region of the viral spike stem. Through in silico molecular docking, peptides with high binding energy were selected. The peptides P-Nat and P-3 were tested for their ability to inhibit RBD-ACE2 interaction using a surrogate ELISA assay. Additionally, P-Nat, P-3, and the stem mimetic peptide P-K2 were evaluated for their antiviral activity against the original SARS-CoV-2 Wuhan strain and the Omicron variant in VeroE6 cell cultures, with IC50 values determined as the primary endpoint.
Results
The ACE2-mimetic peptides significantly inhibited the RBD-ACE2 interaction in the surrogate ELISA assay. P-Nat reduced this interaction by 54%, while P-3 showed an even greater inhibition of 58.77%. These peptides also demonstrated potent antiviral activity against both SARS-CoV-2 variants in VeroE6 cells.
P-Nat exhibited
IC50values of 6.28 μM against the Wuhan strain and 6.26 μM against Omicron, indicating broad efficacy. P-3 showedIC50values of 12.79 μM against Wuhan and 7.27 μM against Omicron. TheHR2-mimetic peptide P-K2 specifically inhibited the Omicron variant with anIC50of 29.17 μM. These findings suggest P-Nat and P-3 are strong candidates for inhibiting both tested variants, with P-K2 showing targeted activity against Omicron.
Key Findings
- Peptide P-Nat inhibited
RBD-ACE2interaction by 54% in a surrogateELISAassay. - Peptide P-3 inhibited
RBD-ACE2interaction by 58.77% in a surrogateELISAassay. - P-Nat inhibited SARS-CoV-2 Wuhan replication with an
IC50of 6.28 μM inVeroE6cells. - P-Nat inhibited SARS-CoV-2 Omicron replication with an
IC50of 6.26 μM inVeroE6cells. - P-K2 inhibited SARS-CoV-2 Omicron replication with an
IC50of 29.17 μM inVeroE6cells.
Why It Matters
This research introduces a promising new class of peptide-based prophylactic agents that directly target SARS-CoV-2 viral entry, offering a potential strategy to prevent infection. By blocking the RBD-ACE2 interaction and viral membrane fusion, these mimetic peptides could provide a critical first line of defense, especially against emerging variants where vaccine efficacy might be reduced. The ability of P-Nat and P-3 to inhibit both Wuhan and Omicron strains suggests a broad-spectrum potential, which is crucial for future pandemic preparedness. While currently in vitro, these findings lay the groundwork for developing intranasal or inhaled peptide formulations that could be administered prior to exposure, offering a novel approach to reduce viral load and disease severity.
sars-cov-2
covid-19
antiviral
peptide
ace2
spike-protein