Specific targeting of the IL-23 receptor, using a novel small peptide noncompetitive antagonist, decreases the inflammatory response
Specific targeting of the IL-23 receptor, using a novel small peptide noncompetitive antagonist, decreases the inflammatory response
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DOI：
10.1152/ajpregu.00540.2013
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发表时间：
2014-11-15
影响因子：
2.8
通讯作者：
Chemtob, Sylvain
中科院分区：
文献类型：
--
作者：
Quiniou, Christiane;Dominguez-Punaro, Maria;Chemtob, Sylvain
IL-23是细胞因子IL-12家族的一部分，由IL-23特异性p19亚基和IL-12共有的p40亚基组成。IL-23特别有助于多种慢性炎性自身免疫性疾病的炎症过程，包括银屑病、多发性硬化、炎性肠病和类风湿性关节炎。到目前为止，一种靶向IL-12和IL-23的共有p40亚基的抗体Ustekinumab在临床上被批准用于治疗银屑病。然而，没有特异性抑制IL-23促炎反应的治疗。我们已经开发了小的IL-23 R特异性拮抗剂，通过设计所有的D-肽产生的灵活的区域的IL-23 R。在这些肽中，我们选择了2305（teeeqqly），因为除了其可溶性特性之外，它还抑制脾细胞中IL-23诱导的STAT 3磷酸化。肽2305特异性结合表达IL-23 R/IL-12 R β 1的HEK-293细胞，而不结合缺乏受体的细胞。肽2305通过调节IL-23 R/IL-12 R β 1表达细胞和Jurkat细胞中IL-23诱导的基因表达显示出功能选择性; 2305不抑制IL-12 R β-IL-12 R β 2 HEK-293细胞中IL-12诱导的细胞因子表达。最后，与抗p40治疗相比，2305在三种体内小鼠模型中有效且选择性地抑制IL-23诱导的炎症：IL-23诱导的耳部炎症、抗CD 40诱导的全身炎症反应和胶原诱导的关节炎。在此，我们描述了一种有效的IL-23 R小肽调节剂2305（teeeqqly）的发现和表征，该调节剂在体内有效。2305可能更方便，更不麻烦，更便宜，最重要的是，比目前治疗炎症的生物制剂更特异，并且可以想象地补充这些慢性和使人衰弱的炎症疾病的实际疗法。
IL-23 is part of the IL-12 family of cytokines and is composed of the p19 subunit specific to IL-23 and the p40 subunit shared with IL-12. IL-23 specifically contributes to the inflammatory process of multiple chronic inflammatory autoimmune disorders, including psoriasis, multiple sclerosis, inflammatory bowel disease, and rheumatoid arthritis. So far, one antibody targeting the shared p40 subunit of IL-12 and IL-23, Ustekinumab, is approved clinically to treat psoriasis. However, there are no treatments inhibiting specifically the IL-23 proinflammatory response. We have developed small IL-23R-specific antagonists by designing all D-peptides arising from flexible regions of IL-23R. Of these peptides, we selected 2305 (teeeqqly), since in addition to its soluble properties, it inhibited IL-23-induced STAT3 phosphorylation in spleen cells. Peptide 2305 specifically binds to IL-23R/IL-12R beta 1-expressing HEK-293 cells and not to cells devoid of the receptor. Peptide 2305 showed functional selectivity by modulating IL-23-induced gene expression in IL-23R/IL-12R beta 1-expressing cells and in Jurkat cells; 2305 does not inhibit IL-12-induced cytokine expression in IL-12R beta-IL-12R beta 2HEK-293 cells. Finally, compared with anti-p40 treatment, 2305 effectively and selectively inhibits IL-23-induced inflammation in three in vivo mouse models: IL-23-induced ear inflammation, anti-CD40-induced systemic inflammatory response, and collagen-induced arthritis. We, hereby, describe the discovery and characterization of a potent IL-23R small-peptide modulator, 2305 (teeeqqly), that is effective in vivo. 2305 may be more convenient, less cumbersome, less costly, and most importantly, more specific than current biologics for the treatment of inflammatory conditions, and conceivably complement the actual therapies for these chronic and debilitating inflammatory diseases.