ArticleScience translational medicine2022
Multivalent designed proteins neutralize SARS-CoV-2 variants of concern and confer protection against infection in mice.
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Article in Science translational medicine, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 77 papers.
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77citing papers in PubMed
11.2field-weighted citation impact, top 1% of its field
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Who cites it
77 citing papers in PubMed, 115 citations in OpenAlex.
- Selective elimination of mast cells via Siglec-6-targeted nanodelivery of drug payload.The Journal of allergy and clinical immunology · 2026Article
- Computational design of potent, broadly neutralizing anti-Nipah virus and Hendra virus miniproteins.bioRxiv : the preprint server for biology · 2026Article
- Inverse FoldDir: Structure-conditioned Protein Sequence Design by Dirichlet Flow Matching.bioRxiv : the preprint server for biology · 2026Article
- Pan-neutralization of parainfluenza viruses by a hemagglutinin-neuraminidase antibody.bioRxiv : the preprint server for biology · 2026Article
- Scalable Production of aPharmaceutics · 2026Article
- Multimerization of a rationally designed nanobody for enhanced avidity toward Aβ42 oligomers.Protein science : a publication of the Protein Society · 2026Article
- Accelerating protein design by scaling experimental characterization.Nature communications · 2026Article
- Computational design of an ultrapotent deltacoronavirus miniprotein inhibitor.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- AI-enabled protein design facilitates future plant research and crop breeding.Plant physiology · 2026Review
- Monitoring biological effects of somatic cell genome editing.Nature reviews. Genetics · 2026Review
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- Design-driven optimization of low-cost reagent formulations for reproducible and high-yielding cell-free gene expression.Nature communications · 2026Article
- Multivalent Protein Nanorings for Broad and Potent SARS-CoV-2 Neutralization.Advanced healthcare materials · 2026Article
- De novo protein design: a transformative frontier in clinical protein applications.Journal of translational medicine · 2026Review
- The computationally designed TRI2-2 miniprotein inhibitor protects against multiple SARS-CoV-2 Omicron variants.Communications biology · 2026Article
- Design of solubly expressed miniaturized SMART MHCs.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
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- High-Throughput De Novo Protein Design Yields Novel Immunomodulatory Agonists.bioRxiv : the preprint server for biology · 2025Article
- Characterizing and engineering post-translational modifications with high-throughput cell-free expression.Nature communications · 2025Article
- Article
17 more citing papers are in PubMed but not listed here.
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Authors and funding
47 authors at 8 institutions in 3 countries.
Andrew C HuntDepartment of Chemical and Biological Engineering, Northwestern University, Evanston, IL 60208, USA.ORCID 0000-0001-9620-593X
James Brett CaseDepartment of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.ORCID 0000-0001-7331-5511
Young-Jun ParkDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.ORCID 0000-0003-2901-6949
Longxing CaoDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.ORCID 0000-0003-4002-3648
Kejia WuDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.ORCID 0000-0002-4532-4290
Alexandra C WallsDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.ORCID 0000-0002-9636-8330
Zhuoming LiuDepartment of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA.ORCID 0000-0001-8198-0976
John E BowenDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.ORCID 0000-0003-3590-9727
Hsien-Wei YehDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.ORCID 0000-0002-9023-776X
Shally SainiDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.ORCID 0000-0002-0430-8788
Louisa HelmsInstitute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA 98109, USA.ORCID 0000-0001-9212-0576
Yan Ting ZhaoDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.ORCID 0000-0001-9230-7066
Tien-Ying HsiangDepartment of Immunology, Center for Innate Immunity and Immune Disease, University of Washington, Seattle, WA 98195, USA.ORCID 0000-0002-4316-4561
Tyler N StarrBasic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.ORCID 0000-0001-6713-6904
Inna GoreshnikDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.ORCID 0000-0002-9254-9249
Lisa KozodoyDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Lauren CarterDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.ORCID 0000-0002-9837-9068
Rashmi RavichandranDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.ORCID 0000-0002-2630-7487
Lydia B GreenAmgen Research, Biologic Discovery, Burnaby, BC V5A 1V7, Canada.
Wadim L MatochkoAmgen Research, Biologic Discovery, Burnaby, BC V5A 1V7, Canada.ORCID 0000-0001-7387-9106
Christy A ThomsonAmgen Research, Biologic Discovery, Burnaby, BC V5A 1V7, Canada.
Bastian VögeliDepartment of Chemical and Biological Engineering, Northwestern University, Evanston, IL 60208, USA.ORCID 0000-0001-7870-7311
Antje KrügerDepartment of Chemical and Biological Engineering, Northwestern University, Evanston, IL 60208, USA.ORCID 0000-0002-8155-0682
Laura A VanBlarganDepartment of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.ORCID 0000-0002-8922-8946
Rita E ChenDepartment of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.ORCID 0000-0002-5100-7750
Baoling YingDepartment of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.ORCID 0000-0002-9344-9004
Adam L BaileyDepartment of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.ORCID 0000-0002-6560-9680
Natasha M KafaiDepartment of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.ORCID 0000-0002-3115-3400
Scott E BoykenDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.ORCID 0000-0002-5378-0632
Ajasja LjubetičDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.ORCID 0000-0002-2171-1579
Natasha EdmanDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.ORCID 0000-0002-7315-7127
George UedaDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.ORCID 0000-0002-9792-7149
Cameron M ChowDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.ORCID 0000-0001-5351-6412
Max JohnsonDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.ORCID 0000-0002-7470-2094
Amin AddetiaDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.ORCID 0000-0001-6703-3841
Mary-Jane NavarroDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.ORCID 0000-0001-5716-459X
Nuttada PanpradistDepartment of Bioengineering, University of Washington, Seattle, WA 98195, USA.ORCID 0000-0002-2733-4110
Michael GaleDepartment of Immunology, Center for Innate Immunity and Immune Disease, University of Washington, Seattle, WA 98195, USA.ORCID 0000-0002-6332-7436
Benjamin S FreedmanInstitute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA 98109, USA.
Jesse D BloomHoward Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA.ORCID 0000-0003-1267-3408
Hannele Ruohola-BakerDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.ORCID 0000-0002-5588-4531
Sean P J WhelanDepartment of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA.ORCID 0000-0003-1564-8590
Lance StewartDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.ORCID 0000-0003-4264-5125
Michael S DiamondDepartment of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.ORCID 0000-0002-8791-3165
David VeeslerDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.ORCID 0000-0002-6019-8675
Michael C JewettDepartment of Chemical and Biological Engineering, Northwestern University, Evanston, IL 60208, USA.ORCID 0000-0003-2948-6211
David BakerDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.ORCID 0000-0001-7896-6217
University of Washington · USWashington University in St. Louis · USHoward Hughes Medical Institute · USNorthwestern University · USDiscovery Institute · USImmune Regulation (United Kingdom) · GBFred Hutch Cancer Center · USUniversity of Wisconsin–Madison · US
Funding
Progenitor Cell Biology Consortium Administrative Coordinating CenterU01HL099997 · NHLBI · UNIVERSITY OF MARYLAND BALTIMORE · PI TERRIN, MICHAEL L · 2009 to 2015
$29.9MTRAINING IN MOLECULAR AND CELLULAR BIOLOGYT32GM007270 · NIGMS · UNIVERSITY OF WASHINGTON · PI RAIBLE, DAVID W · 1985 to 2020
$21.0MSelf Renewal and Differentiation of Human Embryonic Stem CellsP01GM081619 · NIGMS · UNIVERSITY OF WASHINGTON · PI MURRY, CHARLES E · 2007 to 2017
$20.6MUniversity of Washington Arboviral Research Network (UWARN)U01AI151698 · NIAID · UNIVERSITY OF WASHINGTON · PI Michael Gale, PETER MACGARR RABINOWITZ · 2020 to 2026
$13.3MControlling Hematopoietic Lineage Commitment from ESC to PlateletsU01HL099993 · NHLBI · FRED HUTCHINSON CANCER RESEARCH CENTER · PI TOROK-STORB, BEVERLY J. · 2009 to 2015
$8.3MComprehensive Training in Inter-Disciplinary Oral Health ResearchT90DE021984 · NIDCR · UNIVERSITY OF WASHINGTON · PI Robert Aaron Cornell · 2012 to 2026
$7.9MHuman antibody-based countermeasures against the Wuhan Coronavirus SARS-CoV-2R01AI157155 · NIAID · WASHINGTON UNIVERSITY · PI BARIC, RALPH S, CROWE, JAMES E · 2020 to 2024
$6.0MTraining in Cellular & Molecular BiologyT32GM136534 · NIGMS · UNIVERSITY OF WASHINGTON · PI Andrew Atwell Oberst, LARRY S ZWEIFEL · 2021 to 2026
$5.8MV-OLA: point-of-care HIV viral load monitoring and drug resistance testingR01AI145486 · NIAID · UNIVERSITY OF WASHINGTON · PI Barry Ryan Lutz · 2019 to 2026
$5.6MUnraveling the bat humoral immune response against zoonotic viruses to guide the design of next-generation therapeuticsDP1AI158186 · NIAID · UNIVERSITY OF WASHINGTON · PI VEESLER, DAVID · 2020 to 2024
$5.4MJAK-STAT Control of Zika Virus-Induced Fetal InjuryR01AI143265 · NIAID · UNIVERSITY OF WASHINGTON · PI ADAMS WALDORF, KRISTINA M., GALE, MICHAEL · 2019 to 2023
$4.6MInnate Immune Regulation of Zika Virus InfectionR01AI145296 · NIAID · UNIVERSITY OF WASHINGTON · PI COYNE, CAROLYN B, DIAMOND, MICHAEL S · 2019 to 2023
$4.1MHoward Hughes Medical InstituteNCATS NIH HHS UG3 TR002158NCATS NIH HHS UG3 TR003288NHLBI NIH HHS U01 HL099993NHLBI NIH HHS U01 HL099997NIAID NIH HHS DP1 AI158186NIAID NIH HHS HHSN272201700059CNIAID NIH HHS R01 AI143265NIAID NIH HHS R01 AI145296NIAID NIH HHS R01 AI145486NIAID NIH HHS R01 AI157155NIAID NIH HHS R01 AI160052NIAID NIH HHS R21 AI158788NIAID NIH HHS U01 AI151698NIDCR NIH HHS T90 DE021984NIDDK NIH HHS F31 DK130550NIDDK NIH HHS R01 DK117914NIDDK NIH HHS R01 DK130386NIDDK NIH HHS U01 DK127553NIGMS NIH HHS P01 GM081619NIGMS NIH HHS R01 GM083867NIGMS NIH HHS R01 GM097372NIGMS NIH HHS R01 GM120553NIGMS NIH HHS T32 GM007270NIGMS NIH HHS T32 GM136534
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.
Indexed as
COVID-19SARS-CoV-2AnimalsAntibodies, NeutralizingAntibodies, ViralCryoelectron MicroscopyHumansMiceSpike Glycoprotein, CoronavirusAntibodies, NeutralizingAntibodies, ViralSpike Glycoprotein, Coronavirusspike protein, SARS-CoV-2
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