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

doi:10.3389/fphar.2020.00590

Repositioning an Immunomodulatory Drug Vidofludimus as a Farnesoid X Receptor Modulator With Therapeutic Effects on NAFLD

Front Pharmacol. 2020 May 14:11:590. doi: 10.3389/fphar.2020.00590. eCollection 2020.

Authors

Yanlin Zhu¹, Shuangshuang Xu¹, Yi Lu^{1

2}, Yijuan Wei¹, Benqiang Yao¹, Fusheng Guo¹, Xing Zheng¹, Yumeng Wang¹, Ying He³, Lihua Jin^{1

4}, Yong Li¹

Affiliations

¹ State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Innovation Center for Cell Signaling Network, Xiamen University, Xiamen, China.
² Xiamen Key Laboratory of Neonatal Diseases, Xiamen Children's Hospital, Xiamen, China.
³ Laboratory Animal Center, Xiamen University, Xiamen, China.
⁴ Department of Diabetes Complications and Metabolism, Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, USA.

Abstract

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 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 newly established relationships among drugs, targets, and diseases.

Keywords: crystal structure, receptor; drug discovery; drug screening; inflammatory bowel disease (IBD); ligand-binding protein; liver metabolism; nuclear receptor.