{"doi":"10.1101/2020.08.24.264333","title":"Versatile, Multivalent Nanobody Cocktails Efficiently Neutralize SARS-CoV-2","abstract":"The outbreak of COVID-19 has severely impacted global health and the economy. Cost-effective, highly efficacious therapeutics are urgently needed. 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 multiple elite Nbs with picomolar to femtomolar affinities that inhibit viral infection at sub-ng/ml concentration, more potent than some of the best human neutralizing antibodies. We determined a crystal structure of such an elite neutralizing Nb in complex with RBD. Structural proteomics and integrative modeling revealed multiple distinct and non-overlapping epitopes and indicated an array of potential neutralization mechanisms. Structural characterization facilitated the bioengineering of novel multivalent Nb constructs into multi-epitope cocktails 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. These promising agents are readily translated into efficient, cost-effective, and convenient therapeutics to help end this once-in-a-century health crisis.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":120035,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":13,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.948,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":228172,"name":"Sham Nambulli","orcid":"0000-0002-9781-9703","position":1,"is_corresponding":false},{"id":228173,"name":"Zhengyun Xiao","orcid":"0000-0003-2672-1597","position":2,"is_corresponding":false},{"id":314612,"name":"Heng Liu","orcid":"0000-0001-6683-1462","position":3,"is_corresponding":false},{"id":228175,"name":"Zhe Sang","orcid":"0000-0002-1516-2796","position":4,"is_corresponding":false},{"id":218415,"name":"W. Paul Duprex","orcid":"0000-0003-1716-6376","position":5,"is_corresponding":false},{"id":188091,"name":"Dina Schneidman-Duhovny","orcid":null,"position":6,"is_corresponding":false},{"id":471160,"name":"Cheng Zhang","orcid":"0000-0001-6245-6618","position":7,"is_corresponding":false},{"id":484863,"name":"Yi Shi","orcid":"0000-0003-2530-410X","position":8,"is_corresponding":false},{"id":228171,"name":"Yufei Xiang","orcid":"0000-0002-6732-5649","position":0,"is_corresponding":true}],"reference_count":59,"raw_metadata":null,"created_at":"2026-07-18T23:14:13.002105Z","pmid":"32869034","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}