了解人类和动物P2X7受体之间的物种间药物反应变异
Chang-Run Guo1,2, Danqi Sheng3, Ji-Yuan Li4,5
1School of Basic Medicine and Clinical Pharmacy and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
Nature communications
|December 2, 2025
概括
我们通过揭示P2X7药物结合口袋中的结构差异,发现了PSFL1191,一种对人类和大熊猫有选择性的P2X7调节器. 这一发现有助于开发更有效的P2X7疗法.
科学领域:
- 生物化学 生化学
- 药理学 药理学是指药理学的学科.
- 结构生物学 结构生物学
背景情况:
- P2X7受体 (P2X7R) 调节器因人类遗传变异性和特定物种药物反应而面临翻译挑战.
- 了解P2X7R物种间差异的结构基础对于有效的药物开发至关重要.
研究的目的:
- 确定具有特定物种选择性的新型P2X7R调节器.
- 阐明了依赖物种的P2X7R药理学的基础结构机制.
- 使用转基因模型评估选择性P2X7R调节器的治疗潜力.
主要方法:
- 鉴定和表征PSFL1191,一个P2X7R中央口袋 (PCP) 门户网站抑制剂.
- 电子显微镜 (Cryo-EM) 用于确定与抑制剂复合的P2X7R的结构.
- 使用野生型和转基因P2rx7A312V/A312V小鼠进行体内研究,以评估药理效应.
主要成果:
- PSFL1191可以选择性地抑制人类和熊猫的P2X7R,但不能抑制动物的P2X7R.
- 冷-EM结构显示了两个不同的PCP子囊 (PCP1和PCP2) 与差异性抑制剂结合.
- PSFL1191的种类选择性归因于PCP1子口袋中的特定图案.
- 在转基因小鼠中,PSFL1191改变了巨细胞介导的细菌清除和伤口愈合,但没有影响基底生理.
结论:
- 该研究建立了P2X7R调制中物种间药理差异的结构基础.
- 转基因模型是预测P2X7R调节器治疗疗效的宝贵工具.
- 这些发现使P2X7R相关疾病的药物发现更加精确和有效.
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