A polycyclic scaffold identified by structure-based drug design effectively inhibits the human P2X7 receptor
Year: 2025
Type: article
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.
Source: Nature Communications
Institutions: Oregon Health & Science University, Institut de Biomedicina de la Universitat de Barcelona, Universitat de Barcelona, National and Kapodistrian University of Athens, University of Bonn, Universitat Pompeu Fabra, Barcelona Biomedical Research Park, Walther-Straub-Institut für Pharmakologie und Toxikologie, Ludwig-Maximilians-Universität München, Gwangju Institute of Science and Technology
Language: English
Subfield: Physiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: U.S. Department of Energy, U.S. Department of Health and Human Services, American Heart Association, Oregon Health and Science University, Ministerio de Ciencia, Innovación y Universidades, Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, National Institutes of Health, Office of Science, European Regional Development Fund, Agencia Estatal de Investigación, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences, Biological and Environmental Research, Precursory Research for Embryonic Science and Technology
Awards: G1105844351, G1175115578, G1245107021, G1563940424, G2262748287, G300979063, G3480869486, G3547784433, G410571670, SFB 1328: Adeninnukleotide in Immunität und Entzündung, G425668148, G451917667, G491712853, G5080475149, G5539308778, G5967599077, G6221506569, G6585152099, G7054030591, G7084143925, G7319888396, Decoding the Molecular Pharmacology of the P2X7 Receptor, G7805626310, G7863371703, Structure/Function Studies on the Mechanisms of Purinergic Receptor Activation and Antagonism, G8497050386, G9000060489
OpenAlex ID: W4414200700