Structural Basis for Potent Neutralization of Betacoronaviruses by Single-domain Camelid Antibodies
Authors: Daniel Wrapp1#, Dorien De Vlieger2,3,4#
, Kizzmekia S. Corbett5 Gretel M. Torres6 Nianshuang Wang1
, Wander Van Breedam2,3, Kenny Roose2,3, Loes van Schie2,3, VIB-CMB COVID-19 Response Team, Markus Hoffmann Stefan PöhlmannBarney S. Graham5 Nico Callewaert2,3
Ber Schepens2,3,4*, Xavier Saelens2,3,4* and Jason S. McLellan
SUMMARY
Coronaviruses 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. Here, we describe the isolation of singledomain antibodies (VHHs) from a llama immunized with prefusion-stabilized coronavirus spikes. These VHHs neutralize MERS-CoV or SARS-CoV-1 S pseudotyped viruses,respectively. Crystal structures of these VHHs bound to their respective viral targets reveal two distinct epitopes, but both VHHs interfere with receptor binding. We also show cross-reactivity between the SARS-CoV-1 S-directed VHH and SARS-CoV-2 S, and demonstrate that this crossreactive VHH neutralizes SARS-CoV-2 S pseudotyped viruses as a bivalent human IgG Fcfusion. 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.
