SARS-CoV-2 Spike Protein’s Structural Dynamics Affect the Activity of the Bebtelovimab Antibody

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) therapeutic monoclonal antibody bebtelovimab (BEB) was designed to target the spike protein of SARS-CoV-2 and block its entry into host cells via the angiotensin-converting enzyme 2 (ACE2) receptor. In this study, we used molecular modeling to predict interactions of six clinically observed viral S-protein mutants with human ACE2, as well as BEB. We found that some of these mutants could reduce the activity of BEB by changing the relative binding affinity of the viral S-protein with BEB and ACE2. This may contribute to the resistance in viral mutants to BEB. Additionally, we demonstrated that this effect is highly dependent on the dynamic behavior of the involved proteins and their structural variations. We further assessed BEB's activity against SARS-CoV-2 Omicron subvariants BQ.1 and BQ.1.1. Our study provides insights into how mutations may affect BEB's activity, offering valuable information for the development of future therapeutics against rapidly mutating pathogens.