School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China.
College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
Nat Commun. 2024 Mar 7;15(1):2083. doi: 10.1038/s41467-024-46365-x.
Purinergic signaling plays a causal role in the pathogenesis of inflammatory bowel disease. Among purinoceptors, only P2YR is positively correlated with inflammatory score in mucosal biopsies of ulcerative colitis patients, nevertheless, the role of P2YR in ulcerative colitis remains unclear. Here, based on the over-expressions of P2YR in the intestinal epithelium of mice with experimental colitis, we find that male mice lacking P2YR in intestinal epithelial cells exhibit less intestinal injury induced by dextran sulfate sodium. Mechanistically, P2YR deletion limits the transcriptional activity of cAMP-response element binding protein through cAMP/PKA axis, which binds to the promoter of Ripk1, inhibiting necroptosis of intestinal epithelial cells. Furthermore, we design a hierarchical strategy combining virtual screening and chemical optimization to develop a P2YR antagonist HDL-16, which exhibits remarkable anti-colitis effects. Summarily, our study elucidates a previously unknown mechanism whereby P2YR participates in ulcerative colitis, providing a promising therapeutic target for inflammatory bowel disease.
嘌呤能信号在炎症性肠病的发病机制中起因果作用。在嘌呤能受体中，只有 P2YR 与溃疡性结肠炎患者的黏膜活检中的炎症评分呈正相关，但 P2YR 在溃疡性结肠炎中的作用仍不清楚。在这里，基于实验性结肠炎小鼠肠上皮细胞中 P2YR 的过表达，我们发现缺乏肠上皮细胞中 P2YR 的雄性小鼠对葡聚糖硫酸钠诱导的肠道损伤的敏感性降低。在机制上，P2YR 的缺失通过 cAMP/PKA 轴限制了 cAMP 反应元件结合蛋白的转录活性，该蛋白与 Ripk1 的启动子结合，抑制肠上皮细胞的坏死性凋亡。此外，我们设计了一种结合虚拟筛选和化学优化的分层策略来开发 P2YR 拮抗剂 HDL-16，其具有显著的抗结肠炎作用。总之，我们的研究阐明了 P2YR 参与溃疡性结肠炎的一个先前未知的机制，为炎症性肠病提供了一个有前途的治疗靶点。
