Modulation of lymphocyte-mediated tissue repair by rational design of heterocyclic aryl hydrocarbon receptor agonists
Modulation of lymphocyte-mediated tissue repair by rational design of heterocyclic aryl hydrocarbon receptor agonists
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DOI：
10.1126/sciadv.aay8230
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发表时间：
2020-01-01
期刊：
影响因子：
13.6
通讯作者：
Chaikof, Elliot L.
中科院分区：
文献类型：
--
作者：
Chen, Jiaxuan;Haller, Carolyn A.;Chaikof, Elliot L.
芳香烃受体(AHR)是肠道免疫的重要调节因子，也是炎症性肠病(IBD)的治疗靶点。目前的AHR激动剂由于活性低、药代动力学不充分或毒性而不能用于临床翻译。我们合成了一个结构多样的文库，并利用集成的计算和实验研究来发现控制配体-受体相互作用的机制，并设计出有效的药物先导PY109和PY108，它们具有类似药物的物理化学特性，理想的药代动力学曲线，以及低毒。在葡聚糖硫酸钠诱导的结肠炎小鼠模型中，口服化合物通过调节粘膜适应性细胞和固有淋巴样细胞，增加白介素22(IL-22)的产生，并加速粘膜愈合。通过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。从IBD患者的人T细胞中也观察到了显著的IL-22诱导。我们的发现支持合理设计AHR激动剂用于IBD治疗。
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.