Structure-Function Analysis of Resistance to Bamlanivimab by SARS-CoV-2 Variants Kappa, Delta, and Lambda

Area of Science:

• Virology
• Immunology
• Structural Biology

Background:

• Emerging SARS-CoV-2 variants (Kappa, Delta, Lambda) possess concerning mutations in spike protein receptor binding domains (RBDs).
• Mutations like E484Q/L452R, T478K/L452R, and F490S/L452Q are found in the RBDs of these variants.
• While structural analysis suggests mutations may not significantly impede ACE2 binding for viral entry, their impact on antibody evasion is unclear.

Purpose of the Study:

• To investigate the molecular mechanisms by which SARS-CoV-2 variants evade antibody neutralization.
• To assess the impact of specific mutations in Kappa, Delta, and Lambda variants on the binding affinity of the therapeutic antibody LY-CoV555 (Bamlanivimab).
• To validate simulation findings through experimental neutralization assays.

Main Methods:

• All-atom molecular dynamics (MD) simulations were employed to analyze the binding interactions between variant RBDs and LY-CoV555.
• Pseudovirion-based neutralization assays were conducted to evaluate the efficacy of LY-CoV555 against mutant viruses.
• Live virus neutralization assays were performed to confirm the neutralizing activity against the L452R/E484Q mutant.

Main Results:

• MD simulations revealed that E484Q/L452R mutations in the Kappa variant significantly reduce the binding affinity to antibody LY-CoV555.
• Experimental assays confirmed that LY-CoV555 completely lost its neutralizing activity against the L452R/E484Q mutant (Kappa variant).
• Mutations present in the Delta and Lambda variants were also shown to destabilize the binding of RBD to LY-CoV555.

Conclusions:

• The study elucidates the molecular basis for antibody evasion by emerging SARS-CoV-2 variants, specifically concerning the therapeutic antibody LY-CoV555.
• The findings highlight the reduced efficacy of LY-CoV555 against variants carrying mutations like L452R and E484Q.
• This research paves the way for designing more specific therapeutic antibodies or developing effective antibody cocktail treatments against current and future SARS-CoV-2 variants.