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.
- 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.
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.
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