北京大学雷晓光等研究人员合作发现，结构导向的研究发现胆汁酸衍生物用于治疗肝病且不引起瘙痒。2024年10月29日，国际知名学术期刊《细胞》在线发表了这一成果。

据研究人员介绍，慢性瘙痒是肝病患者（如胆汁淤积）中严重影响生活质量的症状。人类G蛋白偶联受体MRGPRX4（hX4）通过胆汁酸（BA）的激活被认为与胆汁淤积瘙痒相关。然而，具体的机制仍不清楚。

研究人员鉴定了在伴有瘙痒症状的胆汁淤积患者中升高的3-磺酸化胆汁酸。研究人员解析了hX4-Gq与3-磷酸脱氧胆酸（DCA-3P）复合物的冷冻电子显微镜结构，DCA-3P是内源性3-磺酸化脱氧胆酸（DCA-3S）的模拟物。该结构揭示了MRGPR家族蛋白中前所未有的配体结合口袋，突显了BA中3-羟基（3-OH）在激活hX4中的重要作用。

基于该结构信息，研究人员设计并开发了缺乏3-OH的胆汁酸衍生物化合物7（C7）。值得注意的是，C7在肝病模型中有效缓解肝损伤和纤维化，同时显著减轻了瘙痒副作用。

附：英文原文

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

Author: Jun Yang, Tianjun Zhao, Junping Fan, Huaibin Zou, Guangyi Lan, Fusheng Guo, Yaocheng Shi, Han Ke, Huasheng Yu, Zongwei Yue, Xin Wang, Yingjie Bai, Shuai Li, Yingjun Liu, Xiaoming Wang, Yu Chen, Yulong Li, Xiaoguang Lei

Issue&Volume: 2024-10-29

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.

DOI: 10.1016/j.cell.2024.10.001

Source: https://www.cell.com/cell/abstract/S0092-8674(24)01149-8