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An ultra-potent synthetic nanobody neutralizes SARS-CoV-2 by locking Spike into an inactive conformation.
Schoof, Michael; Faust, Bryan; Saunders, Reuben A; Sangwan, Smriti; Rezelj, Veronica; Hoppe, Nick; Boone, Morgane; Billesbølle, Christian B; Puchades, Cristina; Azumaya, Caleigh M; Kratochvil, Huong T; Zimanyi, Marcell; Deshpande, Ishan; Liang, Jiahao; Dickinson, Sasha; Nguyen, Henry C; Chio, Cynthia M; Merz, Gregory E; Thompson, Michael C; Diwanji, Devan; Schaefer, Kaitlin; Anand, Aditya A; Dobzinski, Niv; Zha, Beth Shoshana; Simoneau, Camille R; Leon, Kristoffer; White, Kris M; Chio, Un Seng; Gupta, Meghna; Jin, Mingliang; Li, Fei; Liu, Yanxin; Zhang, Kaihua; Bulkley, David; Sun, Ming; Smith, Amber M; Rizo, Alexandrea N; Moss, Frank; Brilot, Axel F; Pourmal, Sergei; Trenker, Raphael; Pospiech, Thomas; Gupta, Sayan; Barsi-Rhyne, Benjamin; Belyy, Vladislav; Barile-Hill, Andrew W; Nock, Silke; Liu, Yuwei; Krogan, Nevan J; Ralston, Corie Y.
Affiliation
  • Schoof M; Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, CA, USA.
  • Faust B; Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, CA, USA.
  • Saunders RA; Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, CA, USA.
  • Sangwan S; Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, CA, USA.
  • Rezelj V; Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, CA, USA.
  • Hoppe N; Quantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, CA, USA.
  • Boone M; Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, CA, USA.
  • Billesbølle CB; Department of Cellular and Molecular Pharmacology, University of California at San Francisco, San Francisco, CA, USA.
  • Puchades C; Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, CA, USA.
  • Azumaya CM; Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, CA, USA.
  • Kratochvil HT; Viral Populations and Pathogenesis Unit, CNRS UMR 3569, Institut Pasteur, 75724, Paris, Cedex 15, France.
  • Zimanyi M; Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, CA, USA.
  • Deshpande I; Quantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, CA, USA.
  • Liang J; Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, CA, USA.
  • Dickinson S; Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, CA, USA.
  • Nguyen HC; Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, CA, USA.
  • Chio CM; Quantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, CA, USA.
  • Merz GE; Quantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, CA, USA.
  • Thompson MC; Quantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, CA, USA.
  • Diwanji D; Quantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, CA, USA.
  • Schaefer K; Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, CA, USA.
  • Anand AA; Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, CA, USA.
  • Dobzinski N; Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, CA, USA.
  • Zha BS; Quantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, CA, USA.
  • Simoneau CR; Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, CA, USA.
  • Leon K; Quantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, CA, USA.
  • White KM; Quantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, CA, USA.
  • Chio US; Quantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, CA, USA.
  • Gupta M; Quantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, CA, USA.
  • Jin M; Quantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, CA, USA.
  • Li F; Quantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, CA, USA.
  • Liu Y; Quantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, CA, USA.
  • Zhang K; Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, CA, USA.
  • Bulkley D; Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, CA, USA.
  • Sun M; Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, CA, USA.
  • Smith AM; Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, CA, USA.
  • Rizo AN; Department of Pulmonary, Critical Care, Allergy and Sleep Medicine, University of California San Francisco, San Francisco, CA 94158, USA.
  • Moss F; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, USA.
  • Brilot AF; J. David Gladstone Institutes, San Francisco, CA, USA.
  • Pourmal S; Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
  • Trenker R; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, USA.
  • Pospiech T; J. David Gladstone Institutes, San Francisco, CA, USA.
  • Gupta S; Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
  • Barsi-Rhyne B; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Belyy V; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Barile-Hill AW; Quantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, CA, USA.
  • Nock S; Quantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, CA, USA.
  • Liu Y; Quantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, CA, USA.
  • Krogan NJ; Quantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, CA, USA.
  • Ralston CY; Quantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, CA, USA.
bioRxiv ; 2020 Aug 17.
Article in En | MEDLINE | ID: mdl-32817938
ABSTRACT
Without an effective prophylactic solution, infections from SARS-CoV-2 continue to rise worldwide with devastating health and economic costs. SARS-CoV-2 gains entry into host cells via an interaction between its Spike protein and the host cell receptor angiotensin converting enzyme 2 (ACE2). Disruption of this interaction confers potent neutralization of viral entry, providing an avenue for vaccine design and for therapeutic antibodies. Here, we develop single-domain antibodies (nanobodies) that potently disrupt the interaction between the SARS-CoV-2 Spike and ACE2. By screening a yeast surface-displayed library of synthetic nanobody sequences, we identified a panel of nanobodies that bind to multiple epitopes on Spike and block ACE2 interaction via two distinct mechanisms. Cryogenic electron microscopy (cryo-EM) revealed that one exceptionally stable nanobody, Nb6, binds Spike in a fully inactive conformation with its receptor binding domains (RBDs) 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 SARS-CoV-2 Spike and picomolar neutralization of SARS-CoV-2 infection. mNb6-tri retains stability and function after aerosolization, lyophilization, and heat treatment. These properties may enable aerosol-mediated delivery of this potent neutralizer directly to the airway epithelia, promising to yield a widely deployable, patient-friendly prophylactic and/or early infection therapeutic agent to stem the worst pandemic in a century.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Language: En Journal: BioRxiv Year: 2020 Type: Article Affiliation country: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Language: En Journal: BioRxiv Year: 2020 Type: Article Affiliation country: United States