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

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  • Additional Information
    • Source:
      Publisher: Cell Press Country of Publication: United States NLM ID: 0413066 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1097-4172 (Electronic) Linking ISSN: 00928674 NLM ISO Abbreviation: Cell Subsets: MEDLINE
    • Publication Information:
      Publication: Cambridge, Ma : Cell Press
      Original Publication: Cambridge, MIT Press.
    • Subject Terms:
      Bile Acids and Salts*/metabolism ; Bile Acids and Salts*/chemistry ; Pruritus*/drug therapy ; Receptors, G-Protein-Coupled*/metabolism ; Receptors, G-Protein-Coupled*/chemistry ; Liver Diseases*/drug therapy ; Liver Diseases*/pathology ; Cholestasis*/drug therapy ; Cholestasis*/metabolism; Humans ; Animals ; Mice ; Male ; Deoxycholic Acid/chemistry ; Deoxycholic Acid/therapeutic use ; Cryoelectron Microscopy ; Mice, Inbred C57BL ; HEK293 Cells ; Liver/metabolism ; Liver/drug effects ; Liver/pathology
    • 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.
      Competing Interests: Declaration of interests The authors declare no competing interests.
      (Copyright © 2024 Elsevier Inc. All rights reserved.)
    • Contributed Indexing:
      Keywords: 3-sulfonated bile acids; MRGPRX4; OCA; bile acids; cholestatic pruritus; cryo-EM structure; deoxycholic acid; farnesoid X receptor; liver diseases; non-alcoholic steatohepatitis
    • Accession Number:
      0 (Bile Acids and Salts)
      0 (Receptors, G-Protein-Coupled)
      005990WHZZ (Deoxycholic Acid)
    • Publication Date:
      Date Created: 20241030 Date Completed: 20241213 Latest Revision: 20241213
    • Publication Date:
      20241214
    • Accession Number:
      10.1016/j.cell.2024.10.001
    • Accession Number:
      39476841