Characterisation of IL-23 receptor antagonists and disease relevant mutants using fluorescent probes.
Characterisation of IL-23 receptor antagonists and disease relevant mutants using fluorescent probes.
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使用荧光探针表征IL-23受体拮抗剂和疾病相关突变体。
DOI：
10.1038/s41467-023-38541-2
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发表时间：
2023-05-19
影响因子：
16.6
通讯作者：
Hill, Stephen J.
中科院分区：
文献类型：
--
作者：
Lay, Charles S.;Isidro-Llobet, Albert;Kilpatrick, Laura E.;Craggs, Peter D.;Hill, Stephen J.
IL-23受体单核苷酸多态性与多种自身炎症性疾病的相关性导致异二聚体受体及其细胞因子配体IL-23成为重要的药物靶点。针对细胞因子的成功的基于抗体的治疗已经获得许可，一类受体的小肽拮抗剂已经进入临床试验。这些多肽拮抗剂可能比现有的抗IL-23疗法具有治疗优势，但对它们的分子药理学知之甚少。在这项研究中，我们使用IL-23的荧光版本来表征活细胞通过NanoBRET竞争分析表达的全长受体的拮抗剂。然后，我们开发了一种针对IL23p19：IL23R界面的环肽荧光探针，并使用该分子来表征进一步的受体拮抗剂。最后，我们利用这些方法研究了免疫损害性的C115Y IL23R突变，证明其作用机制是破坏了IL23p19的结合表位。IL-23受体单核苷酸多态性C115Y与自身炎症性疾病相关。在这里，作者证明了这种突变阻止了荧光环肽和IL-23与IL-23受体的结合。
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.
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影响因子：
3.1
作者：
Jin, Hyun Yong;Tudor, Yanyan;Symons, Antony
通讯作者：
Symons, Antony
影响因子：
32.4
作者：
Oppmann, B;Lesley, R;Kastelein, RA
通讯作者：
Kastelein, RA
DOI：
10.1152/ajpregu.00540.2013
发表时间：
2014-11-15
影响因子：
2.8
作者：
Quiniou, Christiane;Dominguez-Punaro, Maria;Chemtob, Sylvain
通讯作者：
Chemtob, Sylvain
影响因子：
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作者：
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通讯作者：
Zhang, Litao
影响因子：
8.6
作者：
Lay CS;Bridges A;Goulding J;Briddon SJ;Soloviev Z;Craggs PD;Hill SJ
通讯作者：
Hill SJ