De novo design of miniprotein antagonists of cytokine storm inducers

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 Ahlrichs, Sidney Chan, Hillary Tunggal, Michelle DeWitt, Nathaniel Hyams, Lauren Carter, Lance Stewart, Deborah H. Fuller, Ying Mei, K. Christopher Garcia and David Baker ()
Additional contact information
Buwei Huang: University of Washington
Brian Coventry: University of Washington
Marta T. Borowska: Stanford University School of Medicine
Dimitrios C. Arhontoulis: Medical University of South Carolina
Marc Exposit: University of Washington
Mohamad Abedi: University of Washington
Kevin M. Jude: 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
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
K. Christopher Garcia: Stanford University School of Medicine
David Baker: University of Washington

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50919-4

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