2. Academic Validation
  3. A polycyclic scaffold identified by structure-based drug design effectively inhibits the human P2X7 receptor

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

  • Nat Commun. 2025 Sep 15;16(1):8283. doi: 10.1038/s41467-025-62643-8.
Adam C Oken 1,  Andreea L Turcu 2 3,  Eva Tzortzini 4,  Kyriakos Georgiou 4,  Jessica Nagel 5,  Franka G Westermann 5,  Marta Barniol-Xicota 2 6,  Jonas Seidler 7,  Ga-Ram Kim 8,  So-Deok Lee 8,  Annette Nicke 7,  Yong-Chul Kim 8,  Christa E Müller 5,  Antonios Kolocouris 4,  Santiago Vázquez 2 3,  Steven E Mansoor 9 10
Affiliations

Affiliations

  • 1 Department of Chemical Physiology & Biochemistry, Oregon Health & Science University, Portland, OR, USA.
  • 2 Laboratori de Química Farmacèutica, Facultat de Farmàcia i Ciències de l'Alimentació, Universitat de Barcelona, Barcelona, Spain.
  • 3 Institute of Biomedicine of the University of Barcelona, IBUB, Barcelona, Spain.
  • 4 Laboratory of Medicinal Chemistry, Section of Pharmaceutical Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, Greece.
  • 5 PharmaCenter Bonn & Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, Bonn, Germany.
  • 6 Department of Medicine and Life Sciences, Biomedical Research Park (PRBB), Universitat Pompeu Fabra, Barcelona, Spain.
  • 7 Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany.
  • 8 School of Life Sciences, Gwangju Institute of Science and Technology, Buk-gu, Gwangju, Republic of Korea.
  • 9 Department of Chemical Physiology & Biochemistry, Oregon Health & Science University, Portland, OR, USA. mansoors@ohsu.edu.
  • 10 Division of Cardiovascular Medicine, Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, USA. mansoors@ohsu.edu.
PMID: 40954149 DOI: 10.1038/s41467-025-62643-8
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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z