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An ultrapotent synthetic nanobody neutralizes SARS-CoV-2 by stabilizing inactive Spike

Journal Article · · Science
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  1. Univ. of California, San Francisco, CA (United States)
  2. Centre National de la Recherche Scientifique (CNRS), Paris (France)
  3. Icahn School of Medicine at Mount Sinai, New York, NY (United States)
  4. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
  5. Cytiva Life Sciences, Marlborough, MA (United States)
  6. Univ. of California, San Francisco, CA (United States); J. David Gladstone Inst., San Francisco, CA (United States)
+ Show Author Affiliations

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.

Research Organization:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Organization:
USDOE Office of Science (SC); National Institutes of Health (NIH); Laboratoire d'Excellence; Defense Advanced Research Projects Agency (DARPA)
Contributing Organization:
QCRG Structural Biology Consortium
Grant/Contract Number:
AC02-05CH11231
OSTI ID:
1766525
Journal Information:
Science, Journal Name: Science Journal Issue: 6523 Vol. 370; ISSN 0036-8075
Publisher:
AAASCopyright Statement
Country of Publication:
United States
Language:
English

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