Wet-dry-wet drug screen leads to the synthesis of TS1, a novel compound reversing lung fibrosis through inhibition of myofibroblast differentiation.
Wet-dry-wet drug screen leads to the synthesis of TS1, a novel compound reversing lung fibrosis through inhibition of myofibroblast differentiation.
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DOI：
10.1038/s41419-021-04439-4
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发表时间：
2021-12-17
影响因子：
9
通讯作者：
Zacchigna S
中科院分区：
文献类型：
--
作者：
Ring NAR;Volpe MC;Stepišnik T;Mamolo MG;Panov P;Kocev D;Vodret S;Fortuna S;Calabretti A;Rehman M;Colliva A;Marchesan P;Camparini L;Marcuzzo T;Bussani R;Scarabellotto S;Confalonieri M;Pham TX;Ligresti G;Caporarello N;Loffredo FS;Zampieri D;Džeroski S;Zacchigna S
阻止纤维化进展的疗法无效且有限。活化的肌成纤维细胞正在成为纤维化疾病进展的重要靶标。此前，我们对肺成纤维细胞进行了高通量筛选，随后证明抑制肌成纤维细胞活化能够预防博莱霉素治疗小鼠的肺纤维化。高通量筛选是重新利用药物的理想方法，但它们有一个内在的限制，即文库本身的大小。在这里，我们利用“湿”筛选中的数据，并使用“干”机器学习分析来虚拟筛选数百万种化合物，识别出针对肌成纤维细胞分化的新型抗纤维化药物，其中许多在结构上与多巴胺相关。我们体外合成并验证了几种化合物（“湿”），并证实多巴胺及其衍生物 TS1 都是肌成纤维细胞激活的强大抑制剂。我们进一步使用 RNAi 介导的敲低，并证明这两种分子都通过多巴胺受体 3 发挥作用，并通过抑制经典转化生长因子 β 途径发挥抗纤维化作用。此外，分子模型证实了 TS1 能够结合人和小鼠多巴胺受体 3。使用来自特发性肺纤维化患者的原代成纤维细胞证实了 TS1 对人类细胞的抗纤维化作用。最后，TS1 在小鼠肺纤维化模型中预防并逆转了疾病进展。我们的跨学科方法和新型化合物 TS1 都是了解和对抗肺纤维化的有前途的工具。
Therapies halting the progression of fibrosis are ineffective and limited. Activated myofibroblasts are emerging as important targets in the progression of fibrotic diseases. Previously, we performed a high-throughput screen on lung fibroblasts and subsequently demonstrated that the inhibition of myofibroblast activation is able to prevent lung fibrosis in bleomycin-treated mice. High-throughput screens are an ideal method of repurposing drugs, yet they contain an intrinsic limitation, which is the size of the library itself. Here, we exploited the data from our “wet” screen and used “dry” machine learning analysis to virtually screen millions of compounds, identifying novel anti-fibrotic hits which target myofibroblast differentiation, many of which were structurally related to dopamine. We synthesized and validated several compounds ex vivo (“wet”) and confirmed that both dopamine and its derivative TS1 are powerful inhibitors of myofibroblast activation. We further used RNAi-mediated knock-down and demonstrated that both molecules act through the dopamine receptor 3 and exert their anti-fibrotic effect by inhibiting the canonical transforming growth factor β pathway. Furthermore, molecular modelling confirmed the capability of TS1 to bind both human and mouse dopamine receptor 3. The anti-fibrotic effect on human cells was confirmed using primary fibroblasts from idiopathic pulmonary fibrosis patients. Finally, TS1 prevented and reversed disease progression in a murine model of lung fibrosis. Both our interdisciplinary approach and our novel compound TS1 are promising tools for understanding and combating lung fibrosis.
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影响因子：
14.9
作者：
Davies M;Nowotka M;Papadatos G;Dedman N;Gaulton A;Atkinson F;Bellis L;Overington JP
通讯作者：
Overington JP
影响因子：
17.1
作者：
Lagares D;Santos A;Grasberger PE;Liu F;Probst CK;Rahimi RA;Sakai N;Kuehl T;Ryan J;Bhola P;Montero J;Kapoor M;Baron M;Varelas X;Tschumperlin DJ;Letai A;Tager AM
通讯作者：
Tager AM
氟哌啶醇结合的 D-2 多巴胺受体结构激发了亚型选择性配体的发现
影响因子：
16.6
作者：
Fan, Luyu;Tan, Liang;Wang, Sheng
通讯作者：
Wang, Sheng
影响因子：
16.6
作者：
Korbee, Cornelis J.;Heemskerk, Matthias T.;Ottenhoff, Tom H. M.
通讯作者：
Ottenhoff, Tom H. M.
DOI：
10.1016/j.bbrc.2020.06.137
发表时间：
2020-09-03
影响因子：
3.1
作者：
Gaweda, Gabriel;Iyer, Rugmani P.;Bras, Lisandra E. de Castro
通讯作者：
Bras, Lisandra E. de Castro