An ultrapotent synthetic nanobody neutralizes SARS-CoV-2 by stabilizing inactive Spike
Howard Hughes Medical Institute · University of California, San Francisco · +7 more institutions
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…
Citation impact
- FWCI
- 9.81
- Percentile
- 100%
- References
- 65
Authors
147- MSMichael SchoofCorresponding
Howard Hughes Medical Institute, University of California, San Francisco
- BFBryan FaustCorresponding
Howard Hughes Medical Institute, University of California, San Francisco, Quantitative BioSciences
- RAReuben A. SaundersCorresponding
Howard Hughes Medical Institute, University of California, San Francisco
- SSSmriti SangwanCorresponding
Howard Hughes Medical Institute, University of California, San Francisco
- VVVeronica V. RezeljCorresponding
Centre National de la Recherche Scientifique, Institut Pasteur
Topics & keywords
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
- Coronavirus disease 2019 (COVID-19)
- 2019-20 coronavirus outbreak
- Virology
- Spike Protein
- Spike (software development)
- Sars virus
- Betacoronavirus
- Good health and well-being
Funding
- HHHoward Hughes Medical Institute
- UDU.S. Department of EnergyAwards: COVID-19, -AC02-05CH11231, 05CH11231, AC02-05CH11231, DE-AC02, DE-AC02-05CH11231, DE-AC02-
- UDU.S. Department of EducationAward: DE-AC02-05CH11231
- PCPew Charitable Trusts
- DRDamon Runyon Cancer Research Foundation
- HHHelen Hay Whitney Foundation
- SFSandler Foundation
- JFJPB Foundation
- RFRoddenberry Foundation
- SSSearle Scholars Program
- OPOpen Philanthropy ProjectAward: HHSN272201400008C
- ANAgence Nationale de la RechercheAwards: 10-LABX-62-IBEID, DE-AC02-05CH11231, ANR-10-LABX-62-IBEID, ANR-10, ANR-10-LABX-62
- ABAlfred Benzon Foundation
- NINational Institutes of HealthAwards: U19AI142733, HEK293T, S10OD021741, S10OD020054, DP5OD023048, COVID-19, 1R01GM126218, S10OD02174, HHSN272201400008C, DE-AC02-05CH11231
- DADefense Advanced Research Projects AgencyAwards: HR0011-19-2-0020, DE-AC02-05CH11231
- OOOffice of ScienceAwards: AC02-05CH11231, -AC02-05CH11231, DE-AC02
- UOUniversity of California, San Francisco
- NINational Institute of Allergy and Infectious DiseasesAwards: COVID-19, HHSN272201400008C, U19AI142733
- NINational Institute of Neurological Disorders and StrokeAward: F31NS113432
- BABiological and Environmental ResearchAwards: 05CH11231, DE-AC02-05CH11231, AC02-05CH11231
- DSDefense Sciences Office, DARPAAward: HR0011-19-2-0020