Understanding interspecies drug response variations between human and rodent P2X7 receptors

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 P2rx7<sup>A312V/A312V</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.

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Publication Details

Journal
Nature Communications
Published
2025-12-02
DOI
https://doi.org/10.1038/s41467-025-65847-0
Citations
2
Primary Topic
Adenosine and Purinergic Signaling
Type
article
Field-Weighted Citation Impact
2.24
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article

Understanding interspecies drug response variations between human and rodent P2X7 receptors

Yingying Zhao, Ye Huang, Yu Zhou, Danqi Sheng et al.
2 citations
Nature Communications
Adenosine and Purinergic Signaling
2.24
article

Understanding interspecies drug response variations between human and rodent P2X7 receptors

Yingying Zhao, Ye Huang, Yu Zhou, Danqi Sheng, Ye Yu, Peng Cao, Jie Chen, Jia‐Bao Yao, Fei‐Fei Jin, Motoyuki Hattori, Jiang Wang, Tiantian Li, Jian Li, Hong Shu Liu, Rui Zhang, Jiyuan Li, Cheng Shen, Chang-Run Guo, Dongping Wang
article en
2 citations

Abstract

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 P2rx7<sup>A312V/A312V</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.

Nature CommunicationsVol. 16(1)
Nanjing University of Chinese Medicine (CN), China Pharmaceutical University (CN), Chinese Academy of Sciences (CN), Fudan University (CN), Shanghai Institute of Materia Medica (CN), ZheJiang Academy of Agricultural Sciences (CN), University of Chinese Academy of Sciences (CN)
Openalex Percentile: Top 11%
Adenosine and Purinergic Signaling
2.24
DOIOpen Access PDFOpenAlex
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