Abstact

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(A312V/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.