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Cost-effective, efficacious therapeutics are urgently needed against the COVID-19 pandemic Here, we used camelid immunization and proteomics to identify a large repertoire of highly potent neutralizing nanobodies (Nbs) to the SARS-CoV-2 spike (S) protein receptor-binding domain (RBD) We discovered Nbs with picomolar to femtomolar affinities that inhibit viral infection at sub-ng/ml concentration and determined a structure of one of the most potent in complex with RBD Structural proteomics and integrative modeling revealed multiple distinct and non-overlapping epitopes and indicated an array of potential neutralization mechanisms We constructed multivalent Nb constructs that achieved ultrahigh neutralization potency (IC50s as low as 0 058 ng/ml) and may prevent mutational escape These thermostable Nbs can be rapidly produced in bulk from microbes and resist lyophilization, and aerosolization
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Versatile and multivalent nanobodies efficiently neutralize SARS-CoV-2
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