Alpaca nanobodies against SARS-CoV-2: Tyson

SARS-CoV-2 is the etiologic agent of COVID-19, and enters cells through an interaction between the angiotensin converting enzyme 2 (ACE2) and the SARS-CoV-2 spike glycoprotein. Directly preventing this interaction presents an attractive possibility for suppressing SARS-CoV-2 replication. Here we report the isolation and characterization of an alpaca-derived single domain antibody fragment, Ty1, that specifically targets the receptor binding domain (RBD) of the SARS-CoV-2 spike, directly preventing ACE2 engagement. A cryo-electron microscopy structure of the bound complex shows that Ty1 binds to an epitope that is accessible in both the 'up' and 'down' RBD conformations, and sterically prevents spike/ACE2 binding, which is additionally confirmed by mechanistic characterization. This 12.8 kDa nanobody does not need an Fc domain to neutralize SARS-CoV-2, and, unlike monoclonal antibodies, can be expressed in high quantities in bacteria, presenting opportunities for manufacturing at scale. Ty1 is a SARS-CoV-2 antiviral agent.