ArticleScience (New York, N.Y.)2020
An ultrapotent synthetic nanobody neutralizes SARS-CoV-2 by stabilizing inactive Spike.
Open access · hybridAbstract read
In one paragraph
Article in Science (New York, N.Y.), 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 272 papers, 1 of them a synthesis that pooled it.
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272citing papers in PubMed, 1 pooled it
9.7field-weighted citation impact, top 2% of its field
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Who cites it
272 citing papers in PubMed, 1 synthesis or guideline pooled it, 463 citations in OpenAlex.
- Outlook of therapeutic and diagnostic competency of nanobodies against SARS-CoV-2: A systematic review.Analytical biochemistry · 2022Pooled it
- Mechanisms of antibody-dependent enhancement and its research progress in animal coronaviruses.Veterinary research · 2026Review
- ACE2-fused nanobody targeting a cryptic RBD epitope broadly neutralizes SARS-like viruses.Journal of virology · 2026Article
- Advancing Antiviral Design: Integrating Natural Products, Computation and Targeted Delivery.Chemical biology & drug design · 2026Review
- Structure-Guided Design of Proteomimetics Targeting the SARS-CoV-2 S-RBD/hACE2 Interface.Journal of medicinal chemistry · 2026Article
- Hypervariable loop profiling decodes sequence determinants of antibody stability.Nature structural & molecular biology · 2026Article
- Recommendations and considerations for hydroxyl radical protein footprinting-mass spectrometry.Nature methods · 2026Review
- Design and validation of a ribosome display library for synthetic nanobody selection.Advanced biotechnology · 2026Article
- Update and reuse: Structure-guided nanobody evolution against SARS-CoV-2 escape.PLoS pathogens · 2026Article
- Repertoire-scale antibody structural prediction informs therapeutic design.Science advances · 2026Article
- Nanobodies unlock new mechanisms to target G protein-coupled receptors.Molecular pharmacology · 2026Review
- Anti-SARS-CoV-2 VHH and C7C peptide fused with Angiopep-2 efficiently traverse blood-brain barrier model and neutralizes virus.Frontiers in microbiology · 2026Article
- Article
- Nanobodies targeting hnRNPA2/B1 and tau.bioRxiv : the preprint server for biology · 2025Article
- A SARS-CoV-2 entry inhibitor trimerizes to lock the spike protein in a closed conformation.bioRxiv : the preprint server for biology · 2025Article
- Nanobodies Targeting the GP4 Protein Inhibit PRRSV Replication.Microorganisms · 2025Article
- Development of an allosteric adhesion GPCR nanobody with therapeutic potential.Nature chemical biology · 2025Article
- Neutralizing Antibodies vs. Viruses: Interacting Mechanisms and Escape Tactics.Microorganisms · 2025Review
- Nanobodies: a new frontier in influenza virus neutralization.Folia microbiologica · 2025Review
- Bivalent single-domain antibodies show potent mpox virus neutralization through M1R antigen.Communications biology · 2025Article
212 more citing papers are in PubMed but not listed here.
Corrections and comments
- Update of
Authors and funding
57 authors at 7 institutions in 2 countries.
Michael Schoof *Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, CA, USA. michael@walterlab.ucsf.edu peter@walterlab.ucsf.edu aashish.manglik@ucsf.edu.ORCID https://orcid.org/0000-0003-3531-5232
Bryan Faust *Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, CA, USA.ORCID https://orcid.org/0000-0002-4126-6409
Reuben A Saunders *Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, CA, USA.ORCID https://orcid.org/0000-0003-3487-1579
Smriti Sangwan *Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, CA, USA.ORCID https://orcid.org/0000-0003-3772-7142
Veronica Rezelj *Viral Populations and Pathogenesis Unit, CNRS UMR 3569, Institut Pasteur, 75724 Paris Cedex 15, France.ORCID https://orcid.org/0000-0003-1571-8325
Nick HoppeDepartment of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, CA, USA.ORCID https://orcid.org/0000-0003-0265-5337
Morgane BooneHoward Hughes Medical Institute, University of California at San Francisco, San Francisco, CA, USA.ORCID https://orcid.org/0000-0002-7807-5542
Christian B BillesbølleDepartment of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, CA, USA.ORCID https://orcid.org/0000-0001-8084-1552
Cristina PuchadesQuantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, CA, USA.ORCID https://orcid.org/0000-0003-3240-4176
Caleigh M AzumayaQuantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, CA, USA.ORCID https://orcid.org/0000-0002-3484-9921
Huong T KratochvilQuantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, CA, USA.ORCID https://orcid.org/0000-0001-8039-6823
Marcell ZimanyiHoward Hughes Medical Institute, University of California at San Francisco, San Francisco, CA, USA.ORCID https://orcid.org/0000-0003-1981-1244
Ishan DeshpandeDepartment of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, CA, USA.ORCID https://orcid.org/0000-0002-8276-9635
Jiahao LiangDepartment of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, CA, USA.ORCID https://orcid.org/0000-0002-6701-4808
Sasha DickinsonQuantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, CA, USA.ORCID https://orcid.org/0000-0002-8016-1570
Henry C NguyenQuantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, CA, USA.ORCID https://orcid.org/0000-0002-6142-8807
Cynthia M ChioQuantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, CA, USA.ORCID https://orcid.org/0000-0001-8381-1957
Gregory E MerzQuantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, CA, USA.ORCID https://orcid.org/0000-0003-0842-4935
Michael C ThompsonQuantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, CA, USA.ORCID https://orcid.org/0000-0002-6099-2027
Devan DiwanjiQuantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, CA, USA.ORCID https://orcid.org/0000-0002-4285-435X
Kaitlin SchaeferQuantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, CA, USA.ORCID https://orcid.org/0000-0003-4825-1389
Aditya A AnandHoward Hughes Medical Institute, University of California at San Francisco, San Francisco, CA, USA.ORCID https://orcid.org/0000-0002-2643-032X
Niv DobzinskiHoward Hughes Medical Institute, University of California at San Francisco, San Francisco, CA, USA.ORCID https://orcid.org/0000-0003-1106-8118
Beth Shoshana ZhaDepartment of Pulmonary, Critical Care, Allergy and Sleep Medicine, University of California San Francisco, San Francisco, CA, USA.ORCID https://orcid.org/0000-0002-4190-2823
Camille R SimoneauQuantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, USA.ORCID https://orcid.org/0000-0001-9222-8130
Kristoffer LeonQuantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, USA.ORCID https://orcid.org/0000-0003-2424-0458
Kris M WhiteDepartment of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.ORCID https://orcid.org/0000-0003-0889-0506
Un Seng ChioQuantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, CA, USA.ORCID https://orcid.org/0000-0002-5295-2690
Meghna GuptaQuantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, CA, USA.ORCID https://orcid.org/0000-0002-7432-3211
Mingliang JinQuantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, CA, USA.ORCID https://orcid.org/0000-0003-4961-7143
Fei LiQuantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, CA, USA.ORCID https://orcid.org/0000-0003-0720-3129
Yanxin LiuQuantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, CA, USA.ORCID https://orcid.org/0000-0002-2253-3698
Kaihua ZhangQuantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, CA, USA.ORCID https://orcid.org/0000-0003-3734-3624
David BulkleyQuantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, CA, USA.ORCID https://orcid.org/0000-0002-2535-904X
Ming SunQuantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, CA, USA.ORCID https://orcid.org/0000-0002-4413-2502
Amber M SmithQuantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, CA, USA.ORCID https://orcid.org/0000-0003-0669-1589
Alexandrea N RizoQuantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, CA, USA.ORCID https://orcid.org/0000-0003-4813-6348
Frank MossQuantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, CA, USA.ORCID https://orcid.org/0000-0002-6149-6447
Axel F BrilotQuantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, CA, USA.ORCID https://orcid.org/0000-0001-8548-4224
Sergei PourmalQuantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, CA, USA.ORCID https://orcid.org/0000-0002-7537-6016
Raphael TrenkerQuantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, CA, USA.ORCID https://orcid.org/0000-0003-1748-0517
Thomas PospiechQuantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, CA, USA.ORCID https://orcid.org/0000-0003-3630-3794
Sayan GuptaMolecular Biophysics and Integrated Bioimaging and the Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
Benjamin Barsi-RhyneDepartment of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, CA, USA.
Vladislav BelyyHoward Hughes Medical Institute, University of California at San Francisco, San Francisco, CA, USA.ORCID https://orcid.org/0000-0003-2813-8215
Andrew W Barile-HillCytiva Life Sciences, Marlborough, MA, USA.
Silke NockHoward Hughes Medical Institute, University of California at San Francisco, San Francisco, CA, USA.
Yuwei LiuHoward Hughes Medical Institute, University of California at San Francisco, San Francisco, CA, USA.
Nevan J KroganQuantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, CA, USA.ORCID https://orcid.org/0000-0003-4902-337X
Corie Y RalstonMolecular Biophysics and Integrated Bioimaging and the Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
Danielle L SwaneyQuantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, CA, USA.ORCID https://orcid.org/0000-0001-6119-6084
Adolfo García-SastreDepartment of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.ORCID https://orcid.org/0000-0002-6551-1827
Melanie OttQuantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, USA.ORCID https://orcid.org/0000-0002-5697-1274
Marco VignuzziViral Populations and Pathogenesis Unit, CNRS UMR 3569, Institut Pasteur, 75724 Paris Cedex 15, France.ORCID https://orcid.org/0000-0002-4400-771X
QCRG Structural Biology Consortium
Peter WalterHoward Hughes Medical Institute, University of California at San Francisco, San Francisco, CA, USA. michael@walterlab.ucsf.edu peter@walterlab.ucsf.edu aashish.manglik@ucsf.edu.ORCID https://orcid.org/0000-0002-6849-708X
Aashish ManglikDepartment of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, CA, USA. michael@walterlab.ucsf.edu peter@walterlab.ucsf.edu aashish.manglik@ucsf.edu.ORCID https://orcid.org/0000-0002-7173-3741
Quantitative BioSciences · USHoward Hughes Medical Institute · USUniversity of California, San Francisco · USGladstone Institutes · USCentre National de la Recherche Scientifique · FRIcahn School of Medicine at Mount Sinai · USLawrence Berkeley National Laboratory · US
Funding
MEDICAL SCIENTIST TRAINING PROGRAMT32GM007618 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI ANDERSON, MARK S · 1985 to 2020
$29.6MTechnology Development Project - Increasing the complexity of ex vivo human airway models for studying immune response to viral infectionU19AI142733 · NIAID · JACKSON LABORATORY · PI Adolfo Garcia-Sastre, Anna Karolina Palucka · 2019 to 2026
$23.1MRESEARCH PROJECT 2U19AI135990 · NIAID · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Nevan J Krogan · 2018 to 2026
$21.4MSTRUCTURAL BIOLOGY TRAINING PROGRAMT32GM008284 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI KORTEMME, TANJA · 1988 to 2022
$10.1MDevelopment of high-dose time-resolved x-ray footprinting technologies to enable the next level of structural analysis for challenging biological problemsR01GM126218 · NIGMS · UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB · PI RALSTON, CORIE Y · 2018 to 2025
$3.4MIntegrative Program in Complex Biological System (ipCBS)T32EB009383 · NIBIB · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI MARSHALL, WALLACE, WEINER, ORION D · 2009 to 2022
$3.2MEliminating Critical Systematic Errors In Structural Biology With Next-Generation SimulationR01GM124149 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI HOLTON, JAMES M · 2017 to 2024
$2.5MAcquisition of an electron microscope for high-resolution single particle cryo-EMS10OD021741 · OD · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI CHENG, YIFAN · 2016 to 2016
$2.0MMolecular Mechanisms of Iron HomeostasisDP5OD023048 · OD · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI MANGLIK, AASHISH · 2016 to 2020
$2.0MLinux cluster for near atomic resolution single particle cryo-EMS10OD020054 · OD · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI CHENG, YIFAN · 2015 to 2015
$456kMolecular mechanisms of the ACF chromatin remodeling complexF32GM137463 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI CHIO, UN SENG · 2020 to 2022
$201kProton Conduction Pathways in Proton Channel ProteinsK99GM138753 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI KRATOCHVIL, HUONG TRAN · 2020 to 2021
$194kHoward Hughes Medical InstituteNIAID NIH HHS HHSN272201400008CNIAID NIH HHS U19 AI135990NIAID NIH HHS U19 AI142733NIBIB NIH HHS T32 EB009383NIGMS NIH HHS F32 GM125217NIGMS NIH HHS F32 GM137463NIGMS NIH HHS K99 GM138753NIGMS NIH HHS R01 GM124149NIGMS NIH HHS R01 GM126218NIGMS NIH HHS T32 GM007618NIGMS NIH HHS T32 GM008284NIH HHS DP5 OD023048NIH HHS S10 OD020054NIH HHS S10 OD021741NINDS NIH HHS F31 NS113432
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus enters host cells via an interaction between its Spike protein and the host cell receptor angiotensin-converting enzyme 2 (ACE2). By screening a yeast surface-displayed library of synthetic nanobody sequences, we developed nanobodies that disrupt the interaction between Spike and ACE2. Cryo-electron microscopy (cryo-EM) revealed that one nanobody, Nb6, binds Spike in a fully inactive conformation with its receptor binding domains locked into their inaccessible down state, incapable of binding ACE2. Affinity maturation and structure-guided design of multivalency yielded a trivalent nanobody, mNb6-tri, with femtomolar affinity for Spike and picomolar neutralization of SARS-CoV-2 infection. mNb6-tri retains function after aerosolization, lyophilization, and heat treatment, which enables aerosol-mediated delivery of this potent neutralizer directly to the airway epithelia.
Indexed as
Angiotensin-Converting Enzyme 2AnimalsAntibodies, NeutralizingAntibodies, ViralAntibody AffinityChlorocebus aethiopsCryoelectron MicroscopyHumansNeutralization TestsProtein BindingProtein StabilitySingle-Domain AntibodiesSpike Glycoprotein, CoronavirusVero CellsAngiotensin-Converting Enzyme 2Antibodies, NeutralizingAntibodies, ViralSingle-Domain AntibodiesSpike Glycoprotein, Coronavirusspike protein, SARS-CoV-2
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