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- Title
Characterisation of IL-23 receptor antagonists and disease relevant mutants using fluorescent probes.
- Authors
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. The single nucleotide polymorphism C115Y in the IL-23 receptor is associated with autoinflammatory diseases. Here the authors demonstrate that this mutation prevents the binding of a fluorescent cyclic peptide and IL-23 to the IL-23 receptor.
- Subjects
FLUORESCENT probes; SINGLE nucleotide polymorphisms; CYTOKINE receptors; PEPTIDE receptors; BINDING site assay; PEPTIDES; MOLECULAR pharmacology
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-38541-2