Structure-guided discovery of bile acid derivatives for treating liver diseases without causing itch

  • Cell. 2024 Dec 12;187(25):7164-7182.e18. doi: 10.1016/j.cell.2024.10.001.
Jun Yang  1 ,  Tianjun Zhao  2 ,  Junping Fan  3 ,  Huaibin Zou  4 ,  Guangyi Lan  5 ,  Fusheng Guo  1 ,  Yaocheng Shi  3 ,  Han Ke  3 ,  Huasheng Yu  6 ,  Zongwei Yue  1 ,  Xin Wang  7 ,  Yingjie Bai  7 ,  Shuai Li  8 ,  Yingjun Liu  8 ,  Xiaoming Wang  8 ,  Yu Chen  9 ,  Yulong Li  10 ,  Xiaoguang Lei  11
Affiliations
  • 1. Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China.
  • 2. Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China; State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing 100871, China; PKU-IDG/McGovern Institute for Brain Research, New Cornerstone Science Laboratory, Beijing 100871, China.
  • 3. Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
  • 4. Fourth Department of Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China.
  • 5. State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing 100871, China; PKU-IDG/McGovern Institute for Brain Research, New Cornerstone Science Laboratory, Beijing 100871, China.
  • 6. Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 7. Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China; Institute for Cancer Research, Shenzhen Bay Laboratory, Shenzhen 518107, China.
  • 8. Hepaitech (Beijing) Biopharma Technology Co., Ltd., Beijing, China.
  • 9. Fourth Department of Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China. Electronic address: [email protected].
  • 10. Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China; State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing 100871, China; PKU-IDG/McGovern Institute for Brain Research, New Cornerstone Science Laboratory, Beijing 100871, China. Electronic address: [email protected].
  • 11. Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China; Institute for Cancer Research, Shenzhen Bay Laboratory, Shenzhen 518107, China. Electronic address: [email protected].
PMID: 39476841 DOI: 10.1016/j.cell.2024.10.001
Abstract

Chronic itch is a debilitating symptom profoundly impacting the quality of life in patients with liver diseases like cholestasis. Activation of the human G-protein coupled receptor, MRGPRX4 (hX4), by Bile Acids (BAs) is implicated in promoting cholestasis itch. However, the detailed underlying mechanisms remain elusive. Here, we identified 3-sulfated BAs that are elevated in cholestatic patients with itch symptoms. We solved the cryo-EM structure of hX4-Gq in a complex with 3-phosphated deoxycholic acid (DCA-3P), a mimic of the endogenous 3-sulfated deoxycholic acid (DCA-3S). This structure revealed an unprecedented ligand-binding pocket in MRGPR family proteins, highlighting the crucial role of the 3-hydroxyl (3-OH) group on BAs in activating hX4. Guided by this structural information, we designed and developed compound 7 (C7), a BA derivative lacking the 3-OH. Notably, C7 effectively alleviates hepatic injury and fibrosis in Liver Disease Models while significantly mitigating the itch side effects.

Keywords
3-sulfonated bile acids; MRGPRX4; OCA; bile acids; cholestatic pruritus; cryo-EM structure; deoxycholic acid; farnesoid X receptor; liver diseases; non-alcoholic steatohepatitis.
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