Multivalent designed proteins neutralize SARS-CoV-2 variants of concern and confer protection against infection in mice.

Autor: Hunt AC; Department of Chemical and Biological Engineering, Northwestern University, Evanston, IL 60208, USA.; Center for Synthetic Biology, Northwestern University, Evanston, IL 60208, USA., Case JB; Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA., Park YJ; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA., Cao L; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA., Wu K; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA., Walls AC; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA., Liu Z; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA., Bowen JE; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA., Yeh HW; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA., Saini S; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.; Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA 98109, USA., Helms L; Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA 98109, USA.; Division of Nephrology, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98109, USA.; Kidney Research Institute, University of Washington School of Medicine, Seattle, WA 98109, USA.; Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA 98109, USA., Zhao YT; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.; Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA 98109, USA.; Oral Health Sciences, School of Dentistry, University of Washington, Seattle, WA 98195, USA., Hsiang TY; Department of Immunology, Center for Innate Immunity and Immune Disease, University of Washington, Seattle, WA 98195, USA., Starr TN; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA., Goreshnik I; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA., Kozodoy L; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA., Carter L; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA., Ravichandran R; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA., Green LB; Amgen Research, Biologic Discovery, Burnaby, BC V5A 1V7, Canada., Matochko WL; Amgen Research, Biologic Discovery, Burnaby, BC V5A 1V7, Canada., Thomson CA; Amgen Research, Biologic Discovery, Burnaby, BC V5A 1V7, Canada., Vögeli B; Department of Chemical and Biological Engineering, Northwestern University, Evanston, IL 60208, USA.; Center for Synthetic Biology, Northwestern University, Evanston, IL 60208, USA.; Invizyne Technologies Inc., Monrovia, CA 91016, USA., Krüger A; Department of Chemical and Biological Engineering, Northwestern University, Evanston, IL 60208, USA.; Center for Synthetic Biology, Northwestern University, Evanston, IL 60208, USA., VanBlargan LA; Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA., Chen RE; Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA., Ying B; Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA., Bailey AL; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.; Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA., Kafai NM; Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA., Boyken SE; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA., Ljubetič A; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.; Department for Synthetic Biology and Immunology, National Institute of Chemistry, Ljubljana SI-1000, Slovenia., Edman N; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.; Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA 98195, USA.; USA Medical Scientist Training Program, University of Washington, Seattle, WA 98195, USA., Ueda G; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA., Chow CM; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.; Neolukin Therapeutics Inc., Seattle, WA 98102, USA., Johnson M; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA., Addetia A; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.; Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA., Navarro MJ; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA., Panpradist N; Department of Bioengineering, University of Washington, Seattle, WA 98195, USA., Gale M Jr; Department of Immunology, Center for Innate Immunity and Immune Disease, University of Washington, Seattle, WA 98195, USA., Freedman BS; Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA 98109, USA.; Division of Nephrology, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98109, USA.; Kidney Research Institute, University of Washington School of Medicine, Seattle, WA 98109, USA.; Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA 98109, USA.; Department of Bioengineering, University of Washington, Seattle, WA 98195, USA., Bloom JD; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA.; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA., Ruohola-Baker H; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.; Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA 98109, USA.; Oral Health Sciences, School of Dentistry, University of Washington, Seattle, WA 98195, USA.; Department of Bioengineering, University of Washington, Seattle, WA 98195, USA., Whelan SPJ; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA., Stewart L; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA., Diamond MS; Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA.; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.; Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO 63110, USA., Veesler D; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA., Jewett MC; Department of Chemical and Biological Engineering, Northwestern University, Evanston, IL 60208, USA.; Center for Synthetic Biology, Northwestern University, Evanston, IL 60208, USA.; Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA.; Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, USA., Baker D; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA.
Jazyk: angličtina
Zdroj: Science translational medicine [Sci Transl Med] 2022 May 25; Vol. 14 (646), pp. eabn1252. Date of Electronic Publication: 2022 May 25.
DOI: 10.1126/scitranslmed.abn1252
Abstrakt: 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.
Databáze: MEDLINE