The human PXR (pregnane X receptor), a master regulator of drug metabolism, has essential roles in intestinal homeostasis and abrogating inflammation. Existing PXR ligands have substantial off-target toxicity. Based on prior work that established microbial (indole) metabolites as PXR ligands, we proposed microbial metabolite mimicry as a novel strategy for drug discovery that allows exploiting previously unexplored parts of chemical space. Here, we report functionalized indole derivatives as first-in-class non-cytotoxic PXR agonists as a proof of concept for microbial metabolite mimicry. The lead compound, FKK6 (Felix Kopp Kortagere 6), binds directly to PXR protein in solution, induces PXR-specific target gene expression in cells, human organoids, and mice. FKK6 significantly represses pro-inflammatory cytokine production cells and abrogates inflammation in mice expressing the human PXR gene. The development of FKK6 demonstrates for the first time that microbial metabolite mimicry is a viable strategy for drug discovery and opens the door to underexploited regions of chemical space.

中文翻译：

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使用微生物代谢物拟态靶向孕烷 X 受体。

人类 PXR（孕烷 X 受体）是药物代谢的主要调节因子，在肠道稳态和消除炎症中发挥着重要作用。现有的 PXR 配体具有显着的脱靶毒性。基于先前将微生物（吲哚）代谢物建立为 PXR 配体的工作，我们提出微生物代谢物拟态作为药物发现的新策略，允许利用以前未探索的化学空间部分。在这里，我们报告功能化吲哚衍生物作为一流的非细胞毒性 PXR 激动剂，作为微生物代谢物模拟的概念证明。先导化合物 FKK6 (Felix Kopp Kortagere 6) 直接与溶液中的 PXR 蛋白结合，诱导细胞、人类类器官和小鼠中 PXR 特异性靶基因表达。FKK6 显着抑制促炎细胞因子产生细胞并消除表达人 PXR 基因的小鼠的炎症。FKK6 的开发首次证明微生物代谢物模拟是药物发现的可行策略，并为化学空间未充分开发的区域打开了大门。