Selection, biophysical and structural analysis of synthetic nanobodies that effectively neutralize SARS-CoV-2

Tânia F. Custódio, Hrishikesh Das, Daniel J. Sheward, Leo Hanke, Samuel Pazicky, Joanna Pieprzyk, Michèle Sorgenfrei, Martin A. Schroer, Andrey Yu. Gruzinov, Cy M. Jeffries, Melissa A. Graewert, Dmitri I. Svergun, Nikolay Dobrev, Kim Remans, Markus A. Seeger, Gerald M. McInerney, Ben Murrell (), B. Martin Hällberg () and Christian Löw ()
Additional contact information
Tânia F. Custódio: Centre for Structural Systems Biology (CSSB), DESY and European Molecular Biology Laboratory Hamburg
Hrishikesh Das: Centre for Structural Systems Biology (CSSB) and Karolinska Institutet VR-RÅC
Daniel J. Sheward: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet
Leo Hanke: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet
Samuel Pazicky: Centre for Structural Systems Biology (CSSB), DESY and European Molecular Biology Laboratory Hamburg
Joanna Pieprzyk: Centre for Structural Systems Biology (CSSB), DESY and European Molecular Biology Laboratory Hamburg
Michèle Sorgenfrei: University of Zurich
Martin A. Schroer: European Molecular Biology Laboratory (EMBL), Hamburg Outstation c/o Deutsches Elektronen Synchrotron (DESY)
Andrey Yu. Gruzinov: European Molecular Biology Laboratory (EMBL), Hamburg Outstation c/o Deutsches Elektronen Synchrotron (DESY)
Cy M. Jeffries: European Molecular Biology Laboratory (EMBL), Hamburg Outstation c/o Deutsches Elektronen Synchrotron (DESY)
Melissa A. Graewert: European Molecular Biology Laboratory (EMBL), Hamburg Outstation c/o Deutsches Elektronen Synchrotron (DESY)
Dmitri I. Svergun: European Molecular Biology Laboratory (EMBL), Hamburg Outstation c/o Deutsches Elektronen Synchrotron (DESY)
Nikolay Dobrev: European Molecular Biology Laboratory (EMBL) Heidelberg, Protein Expression and Purification Core Facility
Kim Remans: European Molecular Biology Laboratory (EMBL) Heidelberg, Protein Expression and Purification Core Facility
Markus A. Seeger: University of Zurich
Gerald M. McInerney: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet
Ben Murrell: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet
B. Martin Hällberg: Centre for Structural Systems Biology (CSSB) and Karolinska Institutet VR-RÅC
Christian Löw: Centre for Structural Systems Biology (CSSB), DESY and European Molecular Biology Laboratory Hamburg

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: Abstract The coronavirus SARS-CoV-2 is the cause of the ongoing COVID-19 pandemic. Therapeutic neutralizing antibodies constitute a key short-to-medium term approach to tackle COVID-19. However, traditional antibody production is hampered by long development times and costly production. Here, we report the rapid isolation and characterization of nanobodies from a synthetic library, known as sybodies (Sb), that target the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. Several binders with low nanomolar affinities and efficient neutralization activity were identified of which Sb23 displayed high affinity and neutralized pseudovirus with an IC50 of 0.6 µg/ml. A cryo-EM structure of the spike bound to Sb23 showed that Sb23 binds competitively in the ACE2 binding site. Furthermore, the cryo-EM reconstruction revealed an unusual conformation of the spike where two RBDs are in the ‘up’ ACE2-binding conformation. The combined approach represents an alternative, fast workflow to select binders with neutralizing activity against newly emerging viruses.

Date: 2020
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DOI: 10.1038/s41467-020-19204-y

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