Key Points Polyamide targeting IL-23 specifically inhibits the expression of IL-23. Polyamide targeting IL-23 is effective in treating psoriasis and EAU in mice. Autoimmune diseases are a physiological state that immune responses are directed against and damage the body’s own tissues. Numerous studies have demonstrated promising therapeutic effects in certain autoimmune diseases by targeting IL-23/IL-17 axis, mostly through using Abs against IL-23 or IL-17A. Pyrrole–imidazole polyamides are nuclease-resistant compounds that inhibit gene expression through binding to the minor groove of DNA. To develop a novel gene-silencing agent that targets IL-23/IL-17 axis, we designed polyamide that specifically binds to the transcription factor c-Rel–binding site located in the promoter of IL-23p19 subunit. Our study showed that this polyamide is capable of entering into nucleus with high efficiency in dendritic cells and macrophage. In addition, it prevented the binding of c-Rel to the promoter of IL-23p19 in vivo and specifically inhibited the expression of IL-23. More importantly, we demonstrated that this polyamide is therapeutically effective using both the imiquimod-induced psoriasis and experimental autoimmune uveitis mouse models. Taken together, these results indicate that pyrrole–imidazole polyamide targeting IL-23p19 could be a novel and feasible therapeutic strategy for patients with autoimmune diseases.

中文翻译：

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用基因沉默吡咯-咪唑聚酰胺靶向 IL-23 治疗自身免疫性疾病

Key Points 靶向 IL-23 的聚酰胺特异性抑制 IL-23 的表达。靶向 IL-23 的聚酰胺可有效治疗小鼠的银屑病和 EAU。自身免疫性疾病是一种生理状态，免疫反应针对并损害人体自身组织。许多研究表明，通过靶向 IL-23/IL-17 轴，主要是通过使用针对 IL-23 或 IL-17A 的抗体，在某些自身免疫性疾病中具有良好的治疗效果。吡咯-咪唑聚酰胺是核酸酶抗性化合物，可通过与 DNA 小沟结合来抑制基因表达。为了开发一种靶向 IL-23/IL-17 轴的新型基因沉默剂，我们设计了与位于 IL-23p19 亚基启动子中的转录因子 c-Rel 结合位点特异性结合的聚酰胺。我们的研究表明，这种聚酰胺能够高效地进入树突细胞和巨噬细胞的细胞核。此外，它在体内阻止了 c-Rel 与 IL-23p19 启动子的结合，并特异性地抑制了 IL-23 的表达。更重要的是，我们使用咪喹莫特诱导的银屑病和实验性自身免疫性葡萄膜炎小鼠模型证明了这种聚酰胺具有治疗效果。综上所述，这些结果表明，靶向 IL-23p19 的吡咯-咪唑聚酰胺可能是一种针对自身免疫性疾病患者的新颖可行的治疗策略。我们使用咪喹莫特诱导的银屑病和实验性自身免疫性葡萄膜炎小鼠模型证明了这种聚酰胺具有治疗效果。综上所述，这些结果表明，靶向 IL-23p19 的吡咯-咪唑聚酰胺可能是一种针对自身免疫性疾病患者的新颖可行的治疗策略。我们使用咪喹莫特诱导的银屑病和实验性自身免疫性葡萄膜炎小鼠模型证明了这种聚酰胺具有治疗效果。综上所述，这些结果表明，靶向 IL-23p19 的吡咯-咪唑聚酰胺可能是一种针对自身免疫性疾病患者的新颖可行的治疗策略。