Thymic stromal lymphopoietin (TSLP) is a key player in atopic diseases, which has sparked great interest in therapeutically targeting TSLP. Yet, no small-molecule TSLP inhibitors exist due to the challenges of disrupting the protein-protein interaction between TSLP and its receptor. Here, we report the development of small-molecule TSLP receptor inhibitors using virtual screening and docking of >1,000,000 compounds followed by iterative chemical synthesis. BP79 emerged as our lead compound that effectively abrogates TSLP-triggered cytokines at low micromolar concentrations. For in-depth analysis, we developed a human atopic disease drug discovery platform using multi-organ chips. Here, topical application of BP79 onto atopic skin models that were co-cultivated with lung models and Th2 cells effectively suppressed immune cell infiltration and IL-13, IL-4, TSLP, and periostin secretion, while upregulating skin barrier proteins. RNA-Seq analysis corroborate these findings and indicate protective downstream effects on the lungs. To the best of our knowledge, this represents the first report of a potent putative small molecule TSLPR inhibitor which has the potential to expand the therapeutic and preventive options in atopic diseases.

中文翻译：

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通过推定的小分子抑制剂破坏 TSLP-TSLP 受体相互作用，为特应性疾病提供了一种新颖有效的治疗选择。


胸腺基质淋巴细胞生成素 （TSLP） 是特应性疾病的关键参与者，这引发了人们对靶向 TSLP 治疗的巨大兴趣。然而，由于破坏 TSLP 与其受体之间的蛋白质-蛋白质相互作用的挑战，不存在小分子 TSLP 抑制剂。在这里，我们报道了使用 >1,000,000 种化合物的虚拟筛选和对接，然后进行迭代化学合成来开发小分子 TSLP 受体抑制剂。BP79 成为我们的先导化合物，可在低微摩尔浓度下有效消除 TSLP 触发的细胞因子。为了进行深入分析，我们开发了一个使用多器官芯片的人类特应性疾病药物发现平台。在这里，将 BP79 局部应用于与肺模型和 Th2 细胞共培养的特应性皮肤模型上，有效抑制免疫细胞浸润和 IL-13、IL-4、TSLP 和骨膜蛋白分泌，同时上调皮肤屏障蛋白。RNA-Seq 分析证实了这些发现，并表明对肺部的下游保护作用。据我们所知，这代表了一种强效推定的小分子 TSLPR 抑制剂的首次报道，该抑制剂有可能扩大特应性疾病的治疗和预防选择。