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

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.

Ingår i:Nature communications: Springer Science and Business Media LLC11:1, s. 5588-2041-1723

Av författaren/redakt...: Custodio, TF; Das, H; Sheward, DJ; Hanke, L; Pazicky, S; Pieprzyk, J; visa fler...; Sorgenfrei, M; Schroer, MA; Gruzinov, AY; Jeffries, CM; Graewert, MA; Svergun, DI; Dobrev, N; Remans, K; Seeger, MA; McInerney, GM; Murrell, B; Hallberg, BM; Low, C; visa färre...

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