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An ultrapotent synthetic nanobody neutralizes SARS-CoV-2 by stabilizing inactive Spike.
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.
  • Schoof M; 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.
  • 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, 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.
Science ; 370(6523): 1473-1479, 2020 12 18.
Article in English | MEDLINE | ID: covidwho-913670
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antibodies, Neutralizing / Single-Domain Antibodies / Spike Glycoprotein, Coronavirus / Antibodies, Viral Limits: Animals / Humans Language: English Journal: Science Year: 2020 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antibodies, Neutralizing / Single-Domain Antibodies / Spike Glycoprotein, Coronavirus / Antibodies, Viral Limits: Animals / Humans Language: English Journal: Science Year: 2020 Document Type: Article