期刊
CELL REPORTS
卷 36, 期 13, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.celrep.2021.109760
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资金
- Gordon and Betty Moore
- Beckman Foundations
- US Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-76SF00515]
- DOE Office of Biological and Environmental Research
- National Institutes of Health (NIH)
- National Institute of General Medical Sciences (NIGMS) [P30GM133894]
- NIH [P01-AI138938-S1, R01AI078788, R01AI640511]
- George Mason University Fast Grant
- Bulgari Women & Science Fellowship in COVID-19 Research
- Hanna Gray Fellowship Program from the Howard Hughes Medical Institute
- Postdoctoral Enrichment Program from the Burroughs Wellcome Fund
This study characterizes two class 4 anti-RBD antibodies derived from COVID-19 donors that exhibit breadth and potent neutralization of zoonotic coronaviruses and SARS-CoV-2 variants. These antibodies work by occluding the ACE2 binding site and reducing sensitivity to variations in the protein structure.
Many anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) neutralizing antibodies target the angiotensin-converting enzyme 2 (ACE2) binding site on viral spike receptor-binding domains (RBDs). Potent antibodies recognize exposed variable epitopes, often rendering them ineffective against other sarbecoviruses and SARS-CoV-2 variants. Class 4 anti-RBD antibodies against a less-exposed, but moreconserved, cryptic epitope could recognize newly emergent zoonotic sarbecoviruses and variants, but they usually show only weak neutralization potencies. Here, we characterize two class 4 anti-RBD antibodies derived from coronavirus disease 2019 (COVID-19) donors that exhibit breadth and potent neutralization of zoonotic coronaviruses and SARS-CoV-2 variants. C118-RBD and C022-RBD structures reveal orientations that extend from the cryptic epitope to occlude ACE2 binding and CDRH3-RBD main-chain H-bond interactions that extend an RBD beta sheet, thus reducing sensitivity to RBD side-chain changes. A C118-spike trimer structure reveals rotated RBDs that allow access to the cryptic epitope and the potential for intra-spike crosslinking to increase avidity. These studies facilitate vaccine design and illustrate potential advantages of class 4 RBD-binding antibody therapeutics.
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