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Structural Basis for Potent Neutralization of Betacoronaviruses by Single-domain Camelid Antibodies

By Daniel Wrapp, Dorien De Vlieger, Kizzmekia S. Corbett, Gretel M Torres, Wander Van Breedam, Kenny Roose, Loes van Schie, VIB-CMB COVID-19 Response Team, Markus Hoffmann, Stefan Pöhlmann, Barney Graham, Nico Callewaert, Bert Schepens, Xavier Saelens, Jason S. McLellan

Posted 28 Mar 2020
bioRxiv DOI: 10.1101/2020.03.26.010165 (published DOI: 10.1016/j.cell.2020.04.031)

The pathogenic Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus (SARS-CoV-1) and COVID-19 coronavirus (SARS-CoV-2) have all emerged into the human population with devastating consequences. These viruses make use of a large envelope protein called spike (S) to engage host cell receptors and catalyze membrane fusion. Because of the vital role that these S proteins play, they represent a vulnerable target for the development of therapeutics to combat these highly pathogenic coronaviruses. Here, we describe the isolation and characterization of single-domain antibodies (VHHs) from a llama immunized with prefusion-stabilized coronavirus spikes. These VHHs are capable of potently neutralizing MERS-CoV or SARS-CoV-1 S pseudotyped viruses. The crystal structures of these VHHs bound to their respective viral targets reveal two distinct epitopes, but both VHHs block receptor binding. We also show cross-reactivity between the SARS-CoV-1 S-directed VHH and SARS-CoV-2 S, and demonstrate that this cross-reactive VHH is capable of neutralizing SARS-CoV-2 S pseudotyped viruses as a bivalent human IgG Fc-fusion. These data provide a molecular basis for the neutralization of pathogenic betacoronaviruses by VHHs and suggest that these molecules may serve as useful therapeutics during coronavirus outbreaks.

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