An alpaca nanobody neutralizes SARS-CoV-2 by blocking receptor interaction

We report the isolation and characterization of an alpaca-derived, single domain antibody fragment (nanobody) that specifically targets the receptor binding domain (RBD) of the SARS-CoV-2 spike glycoprotein (spike) and potently neutralizes the virus. A cryo-electron microscopy structure of the bound complex at 2.9 [A] resolution reveals that the nanobody (Ty1) binds to an epitope on the RBD accessible in both the "up" and "down" conformations and that Ty1 sterically hinders RBD-ACE2 binding. Mechanistic characterization confirms that Ty1 directly interferes with host cell receptor binding. This 12.8 kDa nanobody binds the SARS-CoV-2 spike with high specificity and affinity, and can be produced in high quantities recombinantly thereby offering potential as a potent and widely accessible SARS-CoV-2 antiviral agent.