De novo design of protein minibinder agonists of TLR3

Chloe S. Adams, Hyojin Kim, Abigail E. Burtner, Dong Sun Lee, Craig Dobbins, Cameron Criswell, Brian Coventry, Adri Tran-Pearson, Ho Min Kim () and Neil P. King ()
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Chloe S. Adams: University of Washington
Hyojin Kim: Institute for Basic Science (IBS)
Abigail E. Burtner: University of Washington
Dong Sun Lee: Institute for Basic Science (IBS)
Craig Dobbins: University of Washington
Cameron Criswell: University of Washington
Brian Coventry: University of Washington
Adri Tran-Pearson: University of Washington
Ho Min Kim: Institute for Basic Science (IBS)
Neil P. King: University of Washington

Nature Communications, 2025, vol. 16, issue 1, 1-11

Abstract: Abstract Toll-like Receptor 3 (TLR3) is a pattern recognition receptor that initiates antiviral immune responses upon binding double-stranded RNA (dsRNA). Several nucleic acid-based TLR3 agonists have been explored clinically as vaccine adjuvants in cancer and infectious disease, but present substantial manufacturing and formulation challenges. Here, we use computational protein design to create novel miniproteins that bind to human TLR3 with nanomolar affinities. Cryo-EM structures of two minibinders in complex with TLR3 reveal that they bind the target as designed, although one partially unfolds due to steric competition with a nearby N-linked glycan. Multivalent forms of both minibinders induce NF-κB signaling in TLR3-expressing cell lines, demonstrating that they may have therapeutically relevant biological activity. Our work provides a foundation for the development of specific, stable, and easy-to-formulate protein-based agonists of TLRs and other pattern recognition receptors.

Date: 2025
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DOI: 10.1038/s41467-025-56369-w

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