PT  - JOURNAL ARTICLE
AU  - Tânia F. Custódio
AU  - Hrishikesh Das
AU  - Daniel J Sheward
AU  - Leo Hanke
AU  - Samuel Pazicky
AU  - Joanna Pieprzyk
AU  - Michèle Sorgenfrei
AU  - Martin Schroer
AU  - Andrey Gruzinov
AU  - Cy Jeffries
AU  - Melissa Graewert
AU  - Dmitri Svergun
AU  - Nikolay Dobrev
AU  - Kim Remans
AU  - Markus A. Seeger
AU  - Gerald M McInerney
AU  - Ben Murrell
AU  - B. Martin Hällberg
AU  - Christian Löw
TI  - Selection, biophysical and structural analysis of synthetic nanobodies that effectively neutralize SARS-CoV-2
AID  - 10.1101/2020.06.23.165415
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.06.23.165415
4099  - http://biorxiv.org/content/early/2020/06/23/2020.06.23.165415.short
4100  - http://biorxiv.org/content/early/2020/06/23/2020.06.23.165415.full
AB  - 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 a novel 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.Competing Interest StatementThe authors have declared no competing interest.