Zheng Huaping, Yu Jingjing, Gao Luhua, Wang Kexin, Xu Zheng, Zeng Zhen, Zheng Kun, Tang Xiaoju, Tian Xiaowen, Zhao Qing, Zhao Jie, Wan Huajing, Cao Zhongwei, Zhang Kang, Cheng Jingqiu, Brosius Jürgen, Zhang Hu, Li Wei, Yan Wei, Shao Zhenhua, Luo Fengming, Deng Cheng
Department of Respiratory and Critical Care Medicine, Center for High Altitude Medicine, Institutes for Systems Genetics, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.
Division of Nephrology and Kidney Research Institute, West China Hospital, Sichuan University, Chengdu, China.
Nat Commun. 2025 Feb 20;16(1):1826. doi: 10.1038/s41467-025-57124-x.
G protein-coupled sphingosine-1-phosphate receptor 1 (S1PR1), a drug target for inflammatory bowel disease (IBD), enables immune cells to egress from lymph nodes, but the treatment increases the risk of immunosuppression. The functional signaling pathway triggered by S1PR1 activation in endothelial cells and its therapeutic application remains unclear. Here, we showed that S1PR1 is highly expressed in endothelial cells of IBD patients and positively correlated with endothelial markers. Gi-biased agonist-SAR247799 activated S1PR1 and reversed pathology in male mouse and organoid IBD models by protecting the integrity of the endothelial barrier without affecting immune cell egress. Cryo-electron microscopy structure of S1PR1-Gi signaling complex bound to SAR247799 with a resolution of 3.47 Å revealed the recognition mode for the biased ligand. With the efficacy of SAR247799 in treating other endothelial dysfunction-associated inflammatory diseases, our study offers mechanistic insights into the Gi-biased S1PR1 agonist and represents a strategy for endothelial dysfunction-associated disease treatment.
G蛋白偶联的1-磷酸鞘氨醇受体1（S1PR1）是炎症性肠病（IBD）的药物靶点，可使免疫细胞从淋巴结中逸出，但该治疗会增加免疫抑制的风险。S1PR1在内皮细胞中激活所触发的功能信号通路及其治疗应用仍不清楚。在这里，我们表明S1PR1在IBD患者的内皮细胞中高表达，并且与内皮标志物呈正相关。偏向Gi的激动剂SAR247799激活S1PR1，并通过保护内皮屏障的完整性而不影响免疫细胞逸出，从而在雄性小鼠和类器官IBD模型中逆转病理状态。与SAR247799结合的S1PR1-Gi信号复合物的冷冻电子显微镜结构，分辨率为3.47Å，揭示了偏向配体的识别模式。鉴于SAR247799在治疗其他内皮功能障碍相关炎症性疾病方面的疗效，我们的研究为偏向Gi的S1PR1激动剂提供了机制见解，并代表了一种治疗内皮功能障碍相关疾病的策略。
