Repositioning an Immunomodulatory Drug Vidofludimus as a Farnesoid X Receptor Modulator With Therapeutic Effects on NAFLD
Yanlin Zhu, Shuangshuang Xu, Yi Lu, Yijuan Wei, Benqiang Yao, Fusheng Guo, Xing Zheng, Yumeng Wang, Ying He, Lihua Jin, Yong Li
Abstract
Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disorder, and yet with no pharmacological treatment received approval 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 FXR by biochemical and crystallographic analysis. We further revealed that vidofludimus exerts in vivo 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 new established relationships among drugs, targets, and diseases.