De novo design of miniprotein antagonists of cytokine storm inducers
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.
Authors
- Kevin M. Jude (ORCID: https://orcid.org/0000-0002-3675-5136)
- Brian Coventry (ORCID: https://orcid.org/0000-0002-6910-6255)
- Michelle DeWitt
- Nathaniel Hyams (ORCID: https://orcid.org/0009-0007-4158-3352)
- Dimitrios C. Arhontoulis (ORCID: https://orcid.org/0000-0002-7959-7692)
- K. Christopher García (ORCID: https://orcid.org/0000-0001-9273-0278)
- Lauren Carter (ORCID: https://orcid.org/0000-0002-9837-9068)
- Buwei Huang (ORCID: https://orcid.org/0000-0002-0762-7178)
- Sidney Chan (ORCID: https://orcid.org/0000-0002-1617-0464)
- Ying Mei (ORCID: https://orcid.org/0000-0002-8508-4076)
- Maggie Ahlrichs (ORCID: https://orcid.org/0000-0002-4793-3890)
- Mohamad H. Abedi (ORCID: https://orcid.org/0000-0001-9717-6288)
- Lance Stewart (ORCID: https://orcid.org/0000-0003-4264-5125)
- Aza Allen (ORCID: https://orcid.org/0000-0001-8053-9070)
- David A. Baker (ORCID: https://orcid.org/0000-0001-7896-6217)
- Samer Halabiya
- Hillary C. Tunggal
- Inna Goreshnik (ORCID: https://orcid.org/0000-0002-9254-9249)
- DEBORAH HEYDENBURG FULLER (ORCID: https://orcid.org/0000-0001-7315-2441)
- Marc Expòsit (ORCID: https://orcid.org/0000-0002-2980-303X)
- Marta T. Borowska (ORCID: https://orcid.org/0000-0002-8223-530X)
- Cami Cordray
Institutions
- Howard Hughes Medical Institute (US)
- Medical University of South Carolina (US)
- University of Washington (US)
- Clemson University (US)
- Stanford University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-08-16
- DOI
- https://doi.org/10.1038/s41467-024-50919-4
- Citations
- 37
- Primary Topic
- Inflammasome and immune disorders
- Type
- article
- Field-Weighted Citation Impact
- 8.65
Funders
- Howard Hughes Medical Institute
- U.S. Department of Energy
- Amgen
- Open Philanthropy Project
- Novo Nordisk
- National Institutes of Health
- Defense Advanced Research Projects Agency
- Defense Threat Reduction Agency
- Office of Science
- National Cancer Institute
- National Institute of General Medical Sciences
- Basic Energy Sciences
- Biological and Environmental Research
- SLAC National Accelerator Laboratory