Inhibition of SARS-CoV-2 pathogenesis by potent peptides designed by the mutation of ACE2 binding region

The outbreak of COVID-19 has resulted in millions of deaths. Despite all attempts that have been made to combat the pandemic, the re-emergence of new variants complicated SARS-CoV-2 eradication. The ongoing global spread of COVID-19 demands the incessant development of novel agents in vaccination, diagnosis, and therapeutics. Targeting receptor-binding domain (RBD) of spike protein by which the virus identifies host receptor, angiotensin-converting enzyme (ACE2), is a promising strategy for curbing viral infection. This study aims to discover novel peptide inhibitors against SARS-CoV-2 entry using computational approaches. The RBD binding domain of ACE2 was extracted and docked against the RBD. MMPBSA calculations revealed the binding energies of each residue in the template. The residues with unfavorable binding energies were considered as mutation spots by OSPREY. Binding energies of the residues in RBD-ACE2 interface was determined by molecular docking. Peptide inhibitors were designed by the mutation of RBD residues in the virus-receptors complex which had unfavorable energies. Peptide tendency for RBD binding, safety, and allergenicity were the criteria based on which the final hits were screened among the initial library. Molecular dynamics simulations also provided information on the mechanisms of inhibitory action in peptides. The results were finally validated by molecular docking simulations to make sure the peptides are capable of hindering virus-host interaction. Our results introduce three peptides P7 (RAWTFLDKFNHEAEDLRYQSSLASWN), P13 (RASTFLDKFNHEAEDLRYQSSLASWN), and P19 (RADTFLDKFNHEAEDLRYQSSLASWN) as potential effective inhibitors of SARS-CoV-2 entry which could be considered in drug development for COVID-19 treatment.