Structural basis for drug discovery targeting the ATP ‐activated cation channel P2X3

Extracellular adenosine triphosphate (ATP) activates P2X3, a trimeric ligand‐gated cation channel highly enriched in peripheral sensory neurons, where it drives the neuronal hypersensitivity that underlies chronic cough and related airway symptoms. Recent structural advances have resolved the conformational landscape of P2X3 (apo, open, and desensitized) and revealed how distinct ligand classes suppress receptor function through different binding modes. This review highlights the structural and pharmacological insights that are integrated to contrast ATP‐competitive orthosteric antagonists (e.g., 2'‐(or‐3')‐O‐(Trinitrophenyl) adenosine 5'‐triphosphate (TNP‐ATP) and A‐317491) with non‐competitive allosteric inhibitors (e.g., gefapixant, camlipixant, and the triazolopyrimidine derivative). Major drug discovery hurdles are also discussed, with an emphasis on taste‐related adverse events arising from the inhibition of the closely related P2X2/3 heterotrimer. Finally, potential strategies are revealed for achieving next‐generation P2X3 therapeutics, including employing time‐resolved cryogenic electron microscopy (cryo‐EM) to capture short‐lived open or activation intermediates, as well as the exploration of alternative biological modalities such as antibody–drug conjugates and peptide therapeutics.