Meanwhile, significant structural deflection induces fewer atomic contacts and an unstable binding mode. The result shows the significantly reduced binding affinity of the Omicron variant for both antibodies, due to the introduction of positively charged residues that greatly weaken their electrostatic interactions. Here, molecular dynamics simulations combined with the interaction entropy method reveal the escape mechanism of Delta/Omicron variants to Bamlanivimab/Etesevimab. Multiple-site mutated SARS-CoV-2 Delta and Omicron variants may trigger immune escape against existing monoclonal antibodies. Consistent with recent experimental reports, our results confirmed that the Omicron variant reduces the neutralizing activity of REGN10933, REGN10987, and REGN10933+REGN10987 with the K417N, N440K, L484A, and Q498R mutations playing a decisive role, while the Delta variant slightly changes their activity. We also studied the effectiveness of these antibodies on the two most dangerous variants Delta and Omicron. The association of REGN10987 with RBD is driven by van der Waals interactions, while electrostatic interactions dominate in the case of REGN10933 and the cocktail. Thus, REGN10933 is probably a better candidate for treating Covid-19 than REGN10987, although the cocktail appears to neutralize the virus more efficiently than REGN10933 or REGN10987 alone. The dissociation constants of REGN10987-RBD and REGN10933-RBD complexes calculated from the coarse-grained simulations are in good agreement with the experimental data. Importantly, the cocktail binds to RBD (simultaneous binding) more strongly than its components. Both computational methods show that REGN10933 binds to RBD more strongly than REGN10987. Here, using all-atom steered molecular dynamics and coarse-grained umbrella sampling, we examine the interactions of the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein with REGN10987 and REGN10933 separately as well as together. Recently, a cocktail of REGN10987 and REGN10933 antibodies was shown to be an excellent candidate for the treatment of Covid-19. Understanding the structures and molecular mechanisms underlying the binding of antibodies to SARS-CoV-2 can contribute to quickly achieving this goal. It can be effectively used or modified for high throughput screening for compounds and biologics that interfere with virus-cell binding and entry to complement other neutralization assays currently in use.Ī promising approach to combat Covid-19 infections is the development of effective antiviral antibodies that target the SARS-CoV-2 spike protein. The assay is rapid, reliable, and highly reproducible, without a requirement for any specialized research reagents or laboratory equipment and should be easy to adapt for use in most investigative and clinical settings. We established two well-behaved stable cell lines, which demonstrated a remarkable correlation with standard cell-free viral pseudotyping for inhibition by convalescent sera, small molecule drugs, and murine anti-spike monoclonal antibodies. We developed a SARS-CoV-2 cell-cell transmission assay that provides a rapid and quantitative readout to assess SARS-CoV-2 Spike hACE2 interaction in the absence of pseudotyped particles or live virus. These relatively modest decreases in antibody neutralization titer for viruses with variant spike proteins suggest that current vaccines will remain protective against the family of Delta variants.Įfficient quantitative assays for measurement of viral replication and infectivity are indispensable to future endeavors to develop prophylactic or therapeutic antiviral drugs or vaccines against SARS-CoV-2. Neutralization resistance to serum antibodies and monoclonal antibodies was mediated by L452R mutation.

Regeneron antibody cocktail neutralized virus with the Delta spike with a 2.6-fold decrease in titer. Convalescent sera and vaccine-elicited antibodies neutralized viruses with Delta spike with 2-5-fold decrease in titer in different donors. To address these issues, we used lentiviruses pseudotyped by variant spikes to measure their neutralization by convalescent sera, vaccine-elicited and Regeneron therapeutic antibodies and ACE2 affinity. Highly transmissible SARS-CoV-2 variants identified in India and designated B.1.617, Kappa (B.1.617.1), Delta (B.1.617.2), B.1.618 and B.1.36.29, contain spike mutations L452R, T478K, E484K, E484Q and N440K located within the spike receptor binding domain and thus could contribute to increased transmissibility and potentially allow re-infection or cause resistance to vaccine-elicited antibody.

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