A polycyclic scaffold identified by structure-based drug design effectively inhibits the human P2X7 receptor

Adam C. Oken, Andreea L. Turcu, Eva Tzortzini, Kyriakos Georgiou, Jessica Nagel, Franka G. Westermann, Marta Barniol-Xicota, Jonas Seidler, Ga-Ram Kim, So-Deok Lee, Annette Nicke, Yong-Chul Kim, Christa E. Müller, Antonios Kolocouris, Santiago Vázquez and Steven E. Mansoor ()
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Adam C. Oken: Oregon Health & Science University
Andreea L. Turcu: Universitat de Barcelona
Eva Tzortzini: National and Kapodistrian University of Athens
Kyriakos Georgiou: National and Kapodistrian University of Athens
Jessica Nagel: University of Bonn
Franka G. Westermann: University of Bonn
Marta Barniol-Xicota: Universitat de Barcelona
Jonas Seidler: Ludwig-Maximilians-Universität München
Ga-Ram Kim: Gwangju Institute of Science and Technology
So-Deok Lee: Gwangju Institute of Science and Technology
Annette Nicke: Ludwig-Maximilians-Universität München
Yong-Chul Kim: Gwangju Institute of Science and Technology
Christa E. Müller: University of Bonn
Antonios Kolocouris: National and Kapodistrian University of Athens
Santiago Vázquez: Universitat de Barcelona
Steven E. Mansoor: Oregon Health & Science University

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract The P2X7 receptor is an ATP-gated ion channel that activates inflammatory pathways involved in diseases such as cancer, atherosclerosis, and neurodegeneration. However, despite the potential benefits of blocking overactive signaling, no P2X7 receptor antagonists have been approved for clinical use. Understanding species-specific pharmacological effects of existing antagonists has been challenging, in part due to the dearth of molecular information on receptor orthologs. Here, to identify distinct molecular features in the human receptor, we determine high-resolution cryo-EM structures of the full-length wild-type human P2X7 receptor in apo closed and ATP-bound open state conformations and draw comparisons with structures of other orthologs. We also report a cryo-EM structure of the human receptor in complex with an adamantane-based inhibitor, which we leverage, in conjunction with functional data and molecular dynamics simulations, to design a potent and selective antagonist with a unique polycyclic scaffold. Functional and structural analysis reveal how this optimized ligand, termed UB-MBX-46, interacts with the classical allosteric pocket of the human P2X7 receptor with subnanomolar potency and high selectivity, revealing its significant therapeutic potential.

Date: 2025
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DOI: 10.1038/s41467-025-62643-8

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