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

Corresponding authors: Bert Schepens, Xavier Saelens and Jason McLellan

Affiliations: Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA; VIB-UGent Center for Medical Biotechnology, VIB, 9052 Ghent, Belgium; Department of Biochemistry and Microbiology, Ghent University, 9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA; Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA; Infection Biology Unit, German Primate Center – Leibniz Institute for Primate Research, 37077 Göttingen, Germany; Faculty of Biology and Psychology, University Göttingen, 37077 Göttingen, Germany.

Publication date: this article was published online on May 5, 2020

DOI: https://doi.org/10.1016/j.cell.2020.04.031

Highlights

Coronaviruses make use of a large envelope protein called spike (S) to engage host cell receptors and catalyze membrane fusion. In this article, the authors describe the isolation of single-domain 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. They also show cross-reactivity between the SARS-CoV-1 S-directed VHH and SARS-CoV-2 S and demonstrate that this cross-reactive VHH neutralizes SARS-CoV-2 S pseudotyped viruses as a bivalent human IgG Fc-fusion.

Nomination Reason

The data present in this article 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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