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Multivalent designed proteins neutralize SARS-CoV-2 variants of concern and confer protection against infection in mice.
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, Bastian; Krüger, Antje; VanBlargan, Laura A; Chen, Rita E; Ying, Baoling; Bailey, Adam L; Kafai, Natasha M; Boyken, Scott E; Ljubetic, Ajasja; Edman, Natasha; Ueda, George; Chow, Cameron M; Johnson, Max; Addetia, Amin; Navarro, Mary-Jane; Panpradist, Nuttada; Gale, Michael; Freedman, Benjamin S; Bloom, Jesse D; Ruohola-Baker, Hannele; Whelan, Sean P J; Stewart, Lance; Diamond, Michael S; Veesler, David; Jewett, Michael C; Baker, David.
  • 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; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA.
  • Helms L; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • Zhao YT; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
  • Hsiang TY; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
  • Starr TN; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
  • Goreshnik I; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
  • Kozodoy L; Institute for Stem Cell and Regenerative 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; Division of Nephrology, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98109, USA.
  • Green LB; Kidney Research Institute, University of Washington School of Medicine, Seattle, WA 98109, USA.
  • Matochko WL; Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA 98109, USA.
  • Thomson CA; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
  • Vögeli B; Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA 98109, USA.
  • Krüger A; Oral Health Sciences, School of Dentistry, University of Washington, Seattle, WA 98195, USA.
  • VanBlargan LA; Department of Immunology, Center for Innate Immunity and Immune Disease, University of Washington, Seattle, WA 98195, USA.
  • Chen RE; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
  • Ying B; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
  • Bailey AL; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
  • Kafai NM; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
  • Boyken SE; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
  • Ljubetic A; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
  • Edman N; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
  • Ueda G; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
  • Chow CM; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
  • Johnson M; Amgen Research, Biologic Discovery, Burnaby, BC V5A 1V7, Canada.
  • Addetia A; Amgen Research, Biologic Discovery, Burnaby, BC V5A 1V7, Canada.
  • Navarro MJ; Amgen Research, Biologic Discovery, Burnaby, BC V5A 1V7, Canada.
  • Panpradist N; Department of Chemical and Biological Engineering, Northwestern University, Evanston, IL 60208, USA.
  • Gale M; Center for Synthetic Biology, Northwestern University, Evanston, IL 60208, USA.
  • Freedman BS; Invizyne Technologies Inc., Monrovia, CA 91016, USA.
  • Bloom JD; Department of Chemical and Biological Engineering, Northwestern University, Evanston, IL 60208, USA.
  • Ruohola-Baker H; Center for Synthetic Biology, Northwestern University, Evanston, IL 60208, USA.
  • Whelan SPJ; Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • Stewart L; Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • Diamond MS; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • Veesler D; Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • Jewett MC; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • Baker D; Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA.
Sci Transl Med ; 14(646): eabn1252, 2022 05 25.
Article in English | MEDLINE | ID: covidwho-1784766
ABSTRACT
New variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to arise and prolong the coronavirus disease 2019 (COVID-19) pandemic. Here, we used a cell-free expression workflow to rapidly screen and optimize constructs containing multiple computationally designed miniprotein inhibitors of SARS-CoV-2. We found the broadest efficacy was achieved with a homotrimeric version of the 75-residue angiotensin-converting enzyme 2 (ACE2) mimic AHB2 (TRI2-2) designed to geometrically match the trimeric spike architecture. Consistent with the design model, in the cryo-electron microscopy structure TRI2-2 forms a tripod at the apex of the spike protein that engaged all three receptor binding domains simultaneously. TRI2-2 neutralized Omicron (B.1.1.529), Delta (B.1.617.2), and all other variants tested with greater potency than the monoclonal antibodies used clinically for the treatment of COVID-19. TRI2-2 also conferred prophylactic and therapeutic protection against SARS-CoV-2 challenge when administered intranasally in mice. Designed miniprotein receptor mimics geometrically arrayed to match pathogen receptor binding sites could be a widely applicable antiviral therapeutic strategy with advantages over antibodies in greater resistance to viral escape and antigenic drift, and advantages over native receptor traps in lower chances of autoimmune responses.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Type of study: Prognostic study Topics: Variants Limits: Animals / Humans Language: English Journal: Sci Transl Med Journal subject: Science / Medicine Year: 2022 Document Type: Article Affiliation country: Scitranslmed.abn1252

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Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Type of study: Prognostic study Topics: Variants Limits: Animals / Humans Language: English Journal: Sci Transl Med Journal subject: Science / Medicine Year: 2022 Document Type: Article Affiliation country: Scitranslmed.abn1252