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Multivalent designed proteins protect against SARS-CoV-2 variants of concern.
Hunt, Andrew C; Case, James Brett; Park, Young-Jun; Cao, Longxing; Wu, Kejia; Walls, Alexandra C; Liu, Zhuoming; Bowen, John E; Yeh, Hsien-Wei; Saini, Shally; Helms, Louisa; Zhao, Yan Ting; Hsiang, Tien-Ying; Starr, Tyler N; Goreshnik, Inna; Kozodoy, Lisa; Carter, Lauren; Ravichandran, Rashmi; Green, Lydia B; Matochko, Wadim L; Thomson, Christy A; Vögeli, Bastain; Krüger-Gericke, Antje; VanBlargan, Laura A; Chen, Rita E; Ying, Baoling; Bailey, Adam L; Kafai, Natasha M; Boyken, Scott; Ljubetic, Ajasja; Edman, Natasha; Ueda, George; Chow, Cameron; Addetia, Amin; Panpradist, Nuttada; Gale, Michael; Freedman, Benjamin S; Lutz, Barry R; Bloom, Jesse D; Ruohola-Baker, Hannele; Whelan, Sean P J; Stewart, Lance; Diamond, Michael S; Veesler, David; Jewett, Michael C; Baker, David.
Afiliação
  • Hunt AC; Department of Chemical and Biological Engineering, Northwestern University, Evanston, IL, 60208, USA.
  • Case JB; Center for Synthetic Biology, Northwestern University, Evanston, IL, 60208, USA.
  • Park YJ; Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.
  • Cao L; Department of Biochemistry, University of Washington, Seattle, WA, 98195, USA.
  • Wu K; Department of Biochemistry, University of Washington, Seattle, WA, 98195, USA.
  • Walls AC; Institute for Protein Design, University of Washington, Seattle, WA, 98195, USA.
  • Liu Z; Department of Biochemistry, University of Washington, Seattle, WA, 98195, USA.
  • Bowen JE; Institute for Protein Design, University of Washington, Seattle, WA, 98195, USA.
  • Yeh HW; Department of Biochemistry, University of Washington, Seattle, WA, 98195, USA.
  • Saini S; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
  • Helms L; Department of Biochemistry, University of Washington, Seattle, WA, 98195, USA.
  • Zhao YT; Department of Biochemistry, University of Washington, Seattle, WA, 98195, USA.
  • Hsiang TY; Institute for Protein Design, University of Washington, Seattle, WA, 98195, USA.
  • Starr TN; Department of Biochemistry, University of Washington, Seattle, WA, 98195, USA.
  • Goreshnik I; Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA, 98109, USA.
  • Kozodoy L; Division of Nephrology and Kidney Research Institute, Department of Medicine, University of Washington School of Medicine, Seattle, WA, 98109, USA.
  • Carter L; Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA, 98109, USA.
  • Ravichandran R; Department of Biochemistry, University of Washington, Seattle, WA, 98195, USA.
  • Green LB; Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA, 98109, USA.
  • Matochko WL; Oral Health Sciences, School of Dentistry, University of Washington, Seattle, WA, 98195, USA.
  • Thomson CA; Department of Immunology, Center for Innate Immunity and Immune Disease, University of Washington, Seattle, WA, 98195, USA.
  • Vögeli B; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.
  • Krüger-Gericke A; Department of Biochemistry, University of Washington, Seattle, WA, 98195, USA.
  • VanBlargan LA; Institute for Protein Design, University of Washington, Seattle, WA, 98195, USA.
  • Chen RE; Department of Biochemistry, University of Washington, Seattle, WA, 98195, USA.
  • Ying B; Institute for Protein Design, University of Washington, Seattle, WA, 98195, USA.
  • Bailey AL; Department of Biochemistry, University of Washington, Seattle, WA, 98195, USA.
  • Kafai NM; Institute for Protein Design, University of Washington, Seattle, WA, 98195, USA.
  • Boyken S; Department of Biochemistry, University of Washington, Seattle, WA, 98195, USA.
  • Ljubetic A; Institute for Protein Design, University of Washington, Seattle, WA, 98195, USA.
  • Edman N; Amgen Research, Biologic Discovery, Burnaby, BC, Canada.
  • Ueda G; Amgen Research, Biologic Discovery, Burnaby, BC, Canada.
  • Chow C; Amgen Research, Biologic Discovery, Burnaby, BC, Canada.
  • Addetia A; Department of Chemical and Biological Engineering, Northwestern University, Evanston, IL, 60208, USA.
  • Panpradist N; Center for Synthetic Biology, Northwestern University, Evanston, IL, 60208, USA.
  • Gale M; Department of Chemical and Biological Engineering, Northwestern University, Evanston, IL, 60208, USA.
  • Freedman BS; Center for Synthetic Biology, Northwestern University, Evanston, IL, 60208, USA.
  • Lutz BR; Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.
  • Bloom JD; Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.
  • Ruohola-Baker H; Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
  • Whelan SPJ; Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.
  • Stewart L; Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
  • Diamond MS; Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.
  • Veesler D; Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
  • Jewett MC; Department of Biochemistry, University of Washington, Seattle, WA, 98195, USA.
  • Baker D; Institute for Protein Design, University of Washington, Seattle, WA, 98195, USA.
bioRxiv ; 2021 Jul 07.
Article em En | MEDLINE | ID: mdl-34268509
ABSTRACT
Escape variants of SARS-CoV-2 are threatening to prolong the COVID-19 pandemic. To address this challenge, we developed multivalent protein-based minibinders as potential prophylactic and therapeutic agents. Homotrimers of single minibinders and fusions of three distinct minibinders were designed to geometrically match the SARS-CoV-2 spike (S) trimer architecture and were optimized by cell-free expression and found to exhibit virtually no measurable dissociation upon binding. Cryo-electron microscopy (cryoEM) showed that these trivalent minibinders engage all three receptor binding domains on a single S trimer. The top candidates neutralize SARS-CoV-2 variants of concern with IC 50 values in the low pM range, resist viral escape, and provide protection in highly vulnerable human ACE2-expressing transgenic mice, both prophylactically and therapeutically. Our integrated workflow promises to accelerate the design of mutationally resilient therapeutics for pandemic preparedness. ONE-SENTENCE

SUMMARY:

We designed, developed, and characterized potent, trivalent miniprotein binders that provide prophylactic and therapeutic protection against emerging SARS-CoV-2 variants of concern.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: BioRxiv Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: BioRxiv Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos