Characterisation of IL-23 receptor antagonists and disease relevant mutants using fluorescent probes

Lay, Charles S.; Isidro-Llobet, Albert; Kilpatrick, Laura E.; Craggs, Peter D.; Hill, Stephen J.

Abstract

Association of single nucleotide polymorphisms in the IL-23 receptor with several auto-inflammatory diseases, led to the heterodimeric receptor and its cytokine-ligand IL-23, becoming important drug targets. Successful antibody-based therapies directed against the cytokine have been licenced and a class of small peptide antagonists of the receptor have entered clinical trials. These peptide antagonists may offer therapeutic advantages over existing anti-IL-23 therapies, but little is known about their molecular pharmacology. In this study, we use a fluorescent version of IL-23 to characterise antagonists of the full-length receptor expressed by living cells using a NanoBRET competition assay. We then develop a cyclic peptide fluorescent probe, specific to the IL23p19:IL23R interface and use this molecule to characterise further receptor antagonists. Finally, we use the assays to study the immunocompromising C115Y IL23R mutation, demonstrating that the mechanism of action is a disruption of the binding epitope for IL23p19.

Citation

Lay, C. S., Isidro-Llobet, A., Kilpatrick, L. E., Craggs, P. D., & Hill, S. J. (2023). Characterisation of IL-23 receptor antagonists and disease relevant mutants using fluorescent probes. Nature Communications, 14, Article 2882. https://doi.org/10.1038/s41467-023-38541-2

• Journal Article Type: Article
• Acceptance Date: May 8, 2023
• Online Publication Date: May 19, 2023
• Publication Date: 2023
• Deposit Date: May 20, 2023
• Publicly Available Date: May 24, 2023
• Journal: Nature Communications
• Electronic ISSN: 2041-1723
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 14
• Article Number: 2882
• DOI: https://doi.org/10.1038/s41467-023-38541-2
• Keywords: General Physics and Astronomy; General Biochemistry, Genetics and Molecular Biology; General Chemistry; Multidisciplinary
• Public URL: https://nottingham-repository.worktribe.com/output/20905556
• Publisher URL: https://www.nature.com/articles/s41467-023-38541-2