De novo design of a stapled peptide targeting SARS-CoV-2 spike protein receptor-binding domain

Although effective vaccines have been developed against SARS-CoV-2, many regions in the world still have low rates of vaccination and new variants with mutations in the viral spike protein have reduced the effectiveness of most available vaccines and treatments. There is an urgent need for a drug to cure this disease and prevent infection. The SARS-CoV-2 virus enters the host cell through protein-protein interaction between the virus's spike protein and the host's angiotensin converting enzyme (ACE2). Using protein design software and molecular dynamics simulations, we have designed a 17-residue peptide (pep39), that binds to the spike protein receptor-binding domain (RBD) and blocks interaction of spike protein with ACE2. We have confirmed the binding activity of the designed peptide for the original spike protein and the delta variant spike protein using micro-cantilever and bio-layer interferometry (BLI) based methods. We also confirmed that pep39 strongly inhibits SARS-CoV-2 virus replication in Vero E6 cells. Taken together these data suggest that a newly designed spike protein RBD blocking peptide pep39 has a potential as a SARS-CoV-2 virus inhibitor.

Automated summary

Despite the development of effective vaccines, low vaccination rates and new variants with spike protein mutations have reduced the effectiveness of current treatments against SARS-CoV-2. A 17-residue peptide called pep39 has been designed to block the interaction between the spike protein and the host's ACE2 receptor, using protein design software and molecular dynamics simulations. Experimental methods have confirmed the binding activity of pep39 to both the original spike protein and the delta variant, and it has shown strong inhibition of SARS-CoV-2 replication in cells. These findings suggest that pep39 has potential as a SARS-CoV-2 inhibitor.