In Silico Design of Peptide-Based SARS-CoV-2 Fusion Inhibitors That Target WT and Mutant Versions of SARS-CoV-2 HR1 Domains

In 2019, novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began infecting humans, resulting in the COVID-19 pandemic. While the push for development of vaccines has yielded some positive results, the emergence of additional variants has led to concerns surrounding sustained vaccine effectiveness as the variants become the dominant strains. This work was undertaken to develop peptide-based antivirals capable of targeting both the wildtype (WT) heptad repeat 1 (HR1) domain of SARS-CoV-2 and the new HR1 variants which have developed. In silico protein mutagenesis, structural characterization, and protein–protein molecular docking were utilized to determine molecular interactions which facilitated binding of peptide-based antivirals targeting the HR1 domains. Molecular dynamics simulations were utilized to predict the final binding affinities of the top five peptide inhibitors designed. This work demonstrated the importance of hydrophobic interactions in the hydrophobic gorge and in the rim of the HR1 domain. Additionally, the placement of charged residues was shown to be essential in maximizing electrostatic interactions. The top five designed peptide inhibitors were all demonstrated to maintain good binding affinity to the WT and the variant HR1 SARS-CoV-2 domains. Therefore, the peptide inhibitors designed in this work could serve as potent antivirals which are effective in targeting both the original SARS-CoV-2 and the HR1 variants that have developed