Zhu Yanlin, Xu Shuangshuang, Lu Yi, Wei Yijuan, Yao Benqiang, Guo Fusheng, Zheng Xing, Wang Yumeng, He Ying, Jin Lihua, Li Yong
State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Innovation Center for Cell Signaling Network, Xiamen University, Xiamen, China.
Xiamen Key Laboratory of Neonatal Diseases, Xiamen Children's Hospital, Xiamen, China.
Front Pharmacol. 2020 May 14;11:590. doi: 10.3389/fphar.2020.00590. eCollection 2020.
Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disorder, and yet with no pharmacological treatment approved worldwide. The repositioning of old drugs provides a safe approach for drug development. Vidofludimus, an inhibitor for dihydroorotate dehydrogenase (DHODH) for the treatment of autoimmune disorders, is herein uncovered as a novel modulator for farnesoid X receptor (FXR) by biochemical and crystallographic analysis. We further revealed that vidofludimus exerts therapeutic effects on dextran sodium sulfate (DSS)-induced colitis in an FXR-dependent manner. Notably, vidofludimus also possesses remarkable beneficial effects in reducing NAFLD by targeting FXR, which may represent a unique approach in developing the treatment for NAFLD. Our findings not only reveal a promising template for the design of novel FXR ligands in treating autoimmune disorders, but also uncover a novel therapeutic effect for vidofludimus on NAFLD based on the newly established relationships among drugs, targets, and diseases.
非酒精性脂肪性肝病（NAFLD）已成为最常见的慢性肝脏疾病，但目前全球尚无获批的药物治疗方法。重新利用旧药为药物研发提供了一种安全的途径。维度氟啶，一种用于治疗自身免疫性疾病的二氢乳清酸脱氢酶（DHODH）抑制剂，通过生化和晶体学分析被发现是法尼醇X受体（FXR）的新型调节剂。我们进一步发现，维度氟啶以FXR依赖的方式对葡聚糖硫酸钠（DSS）诱导的结肠炎发挥治疗作用。值得注意的是，维度氟啶通过靶向FXR在减轻NAFLD方面也具有显著的有益作用，这可能代表了开发NAFLD治疗方法的独特途径。我们的研究结果不仅揭示了设计用于治疗自身免疫性疾病的新型FXR配体的有前景的模板，还基于新建立的药物、靶点和疾病之间的关系，发现了维度氟啶对NAFLD的新治疗作用。
