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Highly synergistic combinations of nanobodies that target SARS-CoV-2 and are resistant to escape.
Mast, Fred D; Fridy, Peter C; Ketaren, Natalia E; Wang, Junjie; Jacobs, Erica Y; Olivier, Jean Paul; Sanyal, Tanmoy; Molloy, Kelly R; Schmidt, Fabian; Rutkowska, Magdalena; Weisblum, Yiska; Rich, Lucille M; Vanderwall, Elizabeth R; Dambrauskas, Nicholas; Vigdorovich, Vladimir; Keegan, Sarah; Jiler, Jacob B; Stein, Milana E; Olinares, Paul Dominic B; Herlands, Louis; Hatziioannou, Theodora; Sather, D Noah; Debley, Jason S; Fenyö, David; Sali, Andrej; Bieniasz, Paul D; Aitchison, John D; Chait, Brian T; Rout, Michael P.
  • Mast FD; Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, United States.
  • Fridy PC; Laboratory of Cellular and Structural Biology, The Rockefeller University, New York, United States.
  • Ketaren NE; Laboratory of Cellular and Structural Biology, The Rockefeller University, New York, United States.
  • Wang J; Laboratory of Mass Spectrometry and Gaseous Ion Chemistry, The Rockefeller University, New York, United States.
  • Jacobs EY; Laboratory of Mass Spectrometry and Gaseous Ion Chemistry, The Rockefeller University, New York, United States.
  • Olivier JP; Department of Chemistry, St. John's University, Queens, United States.
  • Sanyal T; Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, United States.
  • Molloy KR; Department of Bioengineering and Therapeutic Sciences, Department of Pharmaceutical Chemistry, California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, United States.
  • Schmidt F; Laboratory of Mass Spectrometry and Gaseous Ion Chemistry, The Rockefeller University, New York, United States.
  • Rutkowska M; Laboratory of Retrovirology, The Rockefeller University, New York, United States.
  • Weisblum Y; Laboratory of Retrovirology, The Rockefeller University, New York, United States.
  • Rich LM; Laboratory of Retrovirology, The Rockefeller University, New York, United States.
  • Vanderwall ER; Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, United States.
  • Dambrauskas N; Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, United States.
  • Vigdorovich V; Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, United States.
  • Keegan S; Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, United States.
  • Jiler JB; Institute for Systems Genetics and Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, United States.
  • Stein ME; Laboratory of Cellular and Structural Biology, The Rockefeller University, New York, United States.
  • Olinares PDB; Laboratory of Cellular and Structural Biology, The Rockefeller University, New York, United States.
  • Herlands L; Laboratory of Mass Spectrometry and Gaseous Ion Chemistry, The Rockefeller University, New York, United States.
  • Hatziioannou T; AbOde Therapeutics Inc, Woods Hole, United States.
  • Sather DN; Laboratory of Retrovirology, The Rockefeller University, New York, United States.
  • Debley JS; Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, United States.
  • Fenyö D; Department of Pediatrics, University of Washington, Seattle, United States.
  • Sali A; Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, United States.
  • Bieniasz PD; Department of Pediatrics, University of Washington, Seattle, United States.
  • Aitchison JD; Division of Pulmonary and Sleep Medicine, Seattle Children's Hospital, Seattle, United States.
  • Chait BT; Institute for Systems Genetics and Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, United States.
  • Rout MP; Department of Bioengineering and Therapeutic Sciences, Department of Pharmaceutical Chemistry, California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, United States.
Elife ; 102021 12 07.
Article in English | MEDLINE | ID: covidwho-1555771
ABSTRACT
The emergence of SARS-CoV-2 variants threatens current vaccines and therapeutic antibodies and urgently demands powerful new therapeutics that can resist viral escape. We therefore generated a large nanobody repertoire to saturate the distinct and highly conserved available epitope space of SARS-CoV-2 spike, including the S1 receptor binding domain, N-terminal domain, and the S2 subunit, to identify new nanobody binding sites that may reflect novel mechanisms of viral neutralization. Structural mapping and functional assays show that indeed these highly stable monovalent nanobodies potently inhibit SARS-CoV-2 infection, display numerous neutralization mechanisms, are effective against emerging variants of concern, and are resistant to mutational escape. Rational combinations of these nanobodies that bind to distinct sites within and between spike subunits exhibit extraordinary synergy and suggest multiple tailored therapeutic and prophylactic strategies.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Single-Domain Antibodies / Spike Glycoprotein, Coronavirus / SARS-CoV-2 / COVID-19 Topics: Vaccines / Variants Limits: Animals / Humans / Male Language: English Year: 2021 Document Type: Article Affiliation country: ELife.73027

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Single-Domain Antibodies / Spike Glycoprotein, Coronavirus / SARS-CoV-2 / COVID-19 Topics: Vaccines / Variants Limits: Animals / Humans / Male Language: English Year: 2021 Document Type: Article Affiliation country: ELife.73027