Structural Basis for Neutralization of Betacoronaviruses by Llama Antibodies

06/11/2020

Using llamas immunized with prefusion-stabilized betacoronavirus spike proteins, Wrapp et al. identified neutralizing cross-reactive single-domain camelid antibodies, which may serve not only as useful reagents for researchers studying the viruses causing MERS, SARS, and COVID-19, but also potential therapeutic candidates. Crystal structures further revealed how these antibodies bind spike proteins to prevent virus entry into cells. [Image reprinted from Wrapp et al., 2020, Cell 181, 1004–1015 May 28, 2020. Copyright 2020 Elsevier Inc. https://doi.org/10.1016/j.cell.2020.04.031]

Coronaviruses use a large envelope protein called spike (S) to engage host cell receptors and catalyze membrane fusion. S proteins therefore represent a vulnerable target for therapeutics.

Scientists isolated single-domain antibodies (VHHs) from a llama immunized with prefusion-stabilized coronavirus spike proteins. The VHHs neutralized MERS-CoV and SARS-CoV-1 S pseudotyped viruses.

Crystal structures of the VHHs bound to their respective viral targets revealed two distinct epitopes, but both VHHs interfered with receptor binding. There was also cross-reactivity between the SARS-CoV-1 S-directed VHH and SARS-CoV-2 S; the cross-reactive VHH neutralized SARS-CoV-2 S pseudotyped viruses.

The data provide a molecular basis for the neutralization of pathogenic betacoronaviruses by VHHs and suggest that the molecules may serve as useful therapeutics during coronavirus outbreaks.

References

Daniel Wrapp, et al. “Structural Basis for Potent Neutralization of Betacoronaviruses by Single-Domain Camelid Antibodies,” Cell 181 (5), 1004-1015 (2020). DOI: 10.1016/j.cell.2020.04.031