• 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.
• Centre for Structural Systems Biology (CSSB), DESY and European Molecular Biology Laboratory Hamburg, Notkestrasse 85, D-22607, Hamburg, Germany.
• Nat Commun. 2020 Nov 4; 11 (1): 5588.

AbstractThe 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.

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