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<p>Despite intensive development, P2X7 modulators have struggled in translation due to human genetic variability and species-dependent drug responses. Here, we identify PSFL1191, a portal-of-central-pocket (PCP)-site inhibitor selective for human and panda P2X7, but inactive against rodents. Cryo-EM structures revealed two distinct PCP sub-pockets: PCP1, a rigid base pocket demanding precise steric complementarity with PSFL1191, and PCP2, a conserved middle cavity targeted by JNJ-54175446, a clinical candidate unaffected by species differences. Species selectivity maps to a deep PCP1 motif (V312-Y295-M105-F103-P96). In <i>P2rx7</i><sup><i>A312V/A312V</i></sup> mice, PSFL1191 markedly altered macrophage-mediated bacterial clearance and wound healing while preserving basal physiology, effects absent in wild-type animals. Our findings establish the structural basis for interspecies pharmacological divergence in P2X7 modulation and highlight transgenic models as powerful tools for predicting therapeutic efficacy, thereby enabling more precise and efficient drug discovery.</p>

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Understanding interspecies drug response variations between human and rodent P2X7 receptors

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月2日

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  • Chang-Run Guo,
  • Danqi Sheng,
  • Ji-Yuan Li,
  • Tian-Tian Li,
  • Jia-Bao Yao,
  • Rui Zhang,
  • Ye Huang,
  • Ying-Ying Zhao,
  • Dong-Ping Wang,
  • Jie Chen,
  • Jian Li,
  • Jiang Wang,
  • Yu Zhou,
  • Cheng Shen,
  • Fei Jin,
  • Peng Cao,
  • Motoyuki Hattori,
  • Hong Liu,
  • Ye Yu

摘要

Despite intensive development, P2X7 modulators have struggled in translation due to human genetic variability and species-dependent drug responses. Here, we identify PSFL1191, a portal-of-central-pocket (PCP)-site inhibitor selective for human and panda P2X7, but inactive against rodents. Cryo-EM structures revealed two distinct PCP sub-pockets: PCP1, a rigid base pocket demanding precise steric complementarity with PSFL1191, and PCP2, a conserved middle cavity targeted by JNJ-54175446, a clinical candidate unaffected by species differences. Species selectivity maps to a deep PCP1 motif (V312-Y295-M105-F103-P96). In P2rx7A312V/A312V mice, PSFL1191 markedly altered macrophage-mediated bacterial clearance and wound healing while preserving basal physiology, effects absent in wild-type animals. Our findings establish the structural basis for interspecies pharmacological divergence in P2X7 modulation and highlight transgenic models as powerful tools for predicting therapeutic efficacy, thereby enabling more precise and efficient drug discovery.