Structure-Based Epitope Design: Toward a Greater Antibody–SARS-CoV-2 RBD Affinity

[Image: see text] Efficient COVID-19 vaccines are widely acknowledged as the best way to end the global pandemic. SARS-CoV-2 receptor-binding domain (RBD) plays fundamental roles related to cell infection. Antibodies could be developed to target RBD and represent a potential approach for the neutralization of the virus. Epitopes used to produce antibodies are generally linear peptides and thus possess multiple confirmations that do not reflect the actual topology of the targeted part in the native protein. On the other hand, macrocyclic epitopes could constitute closer mimics of the native protein topology and, as such, could generate superior antibodies. In this study, we demonstrated the vital effect of the size and the three-dimensional shape of epitopes on the activity of the developed antibodies against the RBD of SARS-CoV-2. The molecular dynamics studies showed the greater stability of the cyclic epitopes compared with the linear counterparts, which was reflected in the affinity of the produced antibodies. The antibodies developed using macrocyclic epitopes showed superiority with respect to binding to RBD compared to antibodies formed from linear peptides. This study constitutes a roadmap for developing superior antibodies that could be used to inhibit the activity of SARS-CoV-2.