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De novo design of miniprotein antagonists of cytokine storm inducers

Author

Listed:
  • Buwei Huang

    (University of Washington
    University of Washington
    University of Washington)

  • Brian Coventry

    (University of Washington
    University of Washington
    University of Washington)

  • Marta T. Borowska

    (Stanford University School of Medicine)

  • Dimitrios C. Arhontoulis

    (Medical University of South Carolina)

  • Marc Exposit

    (University of Washington
    University of Washington)

  • Mohamad Abedi

    (University of Washington
    University of Washington)

  • Kevin M. Jude

    (Stanford University School of Medicine
    Stanford University School of Medicine)

  • Samer F. Halabiya

    (University of Washington)

  • Aza Allen

    (University of Washington)

  • Cami Cordray

    (University of Washington)

  • Inna Goreshnik

    (University of Washington
    University of Washington
    University of Washington)

  • Maggie Ahlrichs

    (University of Washington)

  • Sidney Chan

    (University of Washington)

  • Hillary Tunggal

    (University of Washington)

  • Michelle DeWitt

    (University of Washington)

  • Nathaniel Hyams

    (Clemson University)

  • Lauren Carter

    (University of Washington)

  • Lance Stewart

    (University of Washington)

  • Deborah H. Fuller

    (University of Washington)

  • Ying Mei

    (Medical University of South Carolina
    Clemson University)

  • K. Christopher Garcia

    (Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University School of Medicine)

  • David Baker

    (University of Washington
    University of Washington
    Stanford University School of Medicine)

Abstract

Cytokine release syndrome (CRS), commonly known as cytokine storm, is an acute systemic inflammatory response that is a significant global health threat. Interleukin-6 (IL-6) and interleukin-1 (IL-1) are key pro-inflammatory cytokines involved in CRS and are hence critical therapeutic targets. Current antagonists, such as tocilizumab and anakinra, target IL-6R/IL-1R but have limitations due to their long half-life and systemic anti-inflammatory effects, making them less suitable for acute or localized treatments. Here we present the de novo design of small protein antagonists that prevent IL-1 and IL-6 from interacting with their receptors to activate signaling. The designed proteins bind to the IL-6R, GP130 (an IL-6 co-receptor), and IL-1R1 receptor subunits with binding affinities in the picomolar to low-nanomolar range. X-ray crystallography studies reveal that the structures of these antagonists closely match their computational design models. In a human cardiac organoid disease model, the IL-1R antagonists demonstrated protective effects against inflammation and cardiac damage induced by IL-1β. These minibinders show promise for administration via subcutaneous injection or intranasal/inhaled routes to mitigate acute cytokine storm effects.

Suggested Citation

  • Buwei Huang & Brian Coventry & Marta T. Borowska & Dimitrios C. Arhontoulis & Marc Exposit & Mohamad Abedi & Kevin M. Jude & Samer F. Halabiya & Aza Allen & Cami Cordray & Inna Goreshnik & Maggie Ahlr, 2024. "De novo design of miniprotein antagonists of cytokine storm inducers," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50919-4
    DOI: 10.1038/s41467-024-50919-4
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    References listed on IDEAS

    as
    1. Herman Schreuder & Chantal Tardif & Susanne Trump-Kallmeyer & Adolfo Soffientini & Edoardo Sarubbi & Ann Akeson & Terry Bowlin & Stephen Yanofsky & Ronald W. Barrett, 1997. "A new cytokine-receptor binding mode revealed by the crystal structure of the IL-1 receptor with an antagonist," Nature, Nature, vol. 386(6621), pages 194-200, March.
    2. Longxing Cao & Brian Coventry & Inna Goreshnik & Buwei Huang & William Sheffler & Joon Sung Park & Kevin M. Jude & Iva Marković & Rameshwar U. Kadam & Koen H. G. Verschueren & Kenneth Verstraete & Sco, 2022. "Design of protein-binding proteins from the target structure alone," Nature, Nature, vol. 605(7910), pages 551-560, May.
    3. Daniel-Adriano Silva & Shawn Yu & Umut Y. Ulge & Jamie B. Spangler & Kevin M. Jude & Carlos Labão-Almeida & Lestat R. Ali & Alfredo Quijano-Rubio & Mikel Ruterbusch & Isabel Leung & Tamara Biary & Ste, 2019. "De novo design of potent and selective mimics of IL-2 and IL-15," Nature, Nature, vol. 565(7738), pages 186-191, January.
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