Aryl hydrocarbon receptor (AHR) is an essential regulator of gut immunity and a promising therapeutic target for inflammatory bowel disease (IBD). Current AHR agonists are inadequate for clinical translation due to low activity, inadequate pharmacokinetics, or toxicity. We synthesized a structurally diverse library and used integrated computational and experimental studies to discover mechanisms governing ligand-receptor interaction and to design potent drug leads PY109 and PY108, which display physiochemical drug-likeness properties, desirable pharmacokinetic profiles, and low toxicity. In a murine model of dextran sulfate sodium-induced colitis, orally administered compounds increase interleukin-22 (IL-22) production and accelerate mucosal healing by modulating mucosal adaptive and innate lymphoid cells. AHR and IL-22 pathway induction was confirmed using RNA sequencing and characterization of the lymphocyte protein-protein interaction network. Significant induction of IL-22 was also observed using human T cells from patients with IBD. Our findings support rationally designed AHR agonists for IBD therapy.

中文翻译：

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通过合理设计杂环芳基烃受体激动剂来调节淋巴细胞介导的组织修复。

芳烃受体（AHR）是肠道免疫的重要调节剂，是炎症性肠病（IBD）的有希望的治疗靶标。由于活性低，药代动力学或毒性不足，当前的AHR激动剂不足以进行临床翻译。我们合成了一个结构多样的文库，并使用集成的计算和实验研究方法来发现控制配体-受体相互作用的机制，并设计了有效的药物前导PY109和PY108，这些药物前导物具有相似的理化性质，所需的药代动力学特征和低毒性。在硫酸葡聚糖钠诱发的结肠炎的小鼠模型中，口服给药的化合物通过调节黏膜适应性和先天淋巴样细胞来增加白介素22（IL-22）的产生并加速黏膜愈合。使用RNA测序和淋巴细胞蛋白-蛋白相互作用网络的表征，证实了AHR和IL-22途径的诱导。使用来自IBD患者的人T细胞也观察到IL-22的显着诱导。我们的发现支持合理设计的IHR治疗AHR激动剂。