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Chronic cough relief by allosteric modulation of P2X3 without taste disturbance

Author

Listed:
  • Chang-Run Guo

    (China Pharmaceutical University
    China Pharmaceutical University
    China Pharmaceutical University)

  • Zhong-Zhe Zhang

    (China Pharmaceutical University)

  • Xing Zhou

    (China Pharmaceutical University)

  • Meng-Yang Sun

    (China Pharmaceutical University)

  • Tian-Tian Li

    (China Pharmaceutical University)

  • Yun-Tao Lei

    (China Pharmaceutical University)

  • Yu-Hao Gao

    (China Pharmaceutical University)

  • Qing-Quan Li

    (China Pharmaceutical University)

  • Chen-Xi Yue

    (China Pharmaceutical University)

  • Yu Gao

    (China Pharmaceutical University)

  • Yi-Yu Lin

    (China Pharmaceutical University)

  • Cui-Yun Hao

    (China Pharmaceutical University)

  • Chang-Zhu Li

    (Hunan Academy of Forestry)

  • Peng Cao

    (Nanjing University of Chinese Medicine)

  • Michael X. Zhu

    (The University of Texas Health Science Center at Houston)

  • Ming-Qiang Rong

    (Hunan Normal University)

  • Wen-Hui Wang

    (China Pharmaceutical University)

  • Ye Yu

    (China Pharmaceutical University
    China Pharmaceutical University)

Abstract

P2X receptors are cation channels that sense extracellular ATP. Many therapeutic candidates targeting P2X receptors have begun clinical trials or acquired approval for the treatment of refractory chronic cough (RCC) and other disorders. However, the present negative allosteric modulation of P2X receptors is primarily limited to the central pocket or the site below the left flipper domain. Here, we uncover a mechanism of allosteric regulation of P2X3 in the inner pocket of the head domain (IP-HD), and show that the antitussive effects of quercetin and PSFL2915 (our nM-affinity P2X3 inhibitor optimized based on quercetin) on male mice and guinea pigs were achieved by preventing allosteric changes of IP-HD in P2X3. While being therapeutically comparable to the newly licensed P2X3 RCC drug gefapixant, quercetin and PSFL2915 do not have an adverse effect on taste as gefapixant does. Thus, allosteric modulation of P2X3 via IP-HD may be a druggable strategy to alleviate RCC.

Suggested Citation

  • Chang-Run Guo & Zhong-Zhe Zhang & Xing Zhou & Meng-Yang Sun & Tian-Tian Li & Yun-Tao Lei & Yu-Hao Gao & Qing-Quan Li & Chen-Xi Yue & Yu Gao & Yi-Yu Lin & Cui-Yun Hao & Chang-Zhu Li & Peng Cao & Michae, 2023. "Chronic cough relief by allosteric modulation of P2X3 without taste disturbance," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41495-0
    DOI: 10.1038/s41467-023-41495-0
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    References listed on IDEAS

    as
    1. Fan Yang & Xian Xiao & Bo Hyun Lee & Simon Vu & Wei Yang & Vladimir Yarov-Yarovoy & Jie Zheng, 2018. "The conformational wave in capsaicin activation of transient receptor potential vanilloid 1 ion channel," Nature Communications, Nature, vol. 9(1), pages 1-9, December.
    2. Motoyuki Hattori & Eric Gouaux, 2012. "Molecular mechanism of ATP binding and ion channel activation in P2X receptors," Nature, Nature, vol. 485(7397), pages 207-212, May.
    3. Toshimitsu Kawate & Jennifer Carlisle Michel & William T. Birdsong & Eric Gouaux, 2009. "Crystal structure of the ATP-gated P2X4 ion channel in the closed state," Nature, Nature, vol. 460(7255), pages 592-598, July.
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    Cited by:

    1. Yi-Yu Lin & Yan Lu & Chun-Yun Li & Xue-Fei Ma & Miao-Qing Shao & Yu-Hao Gao & Yu-Qing Zhang & Hai-Ning Jiang & Yan Liu & Yang Yang & Li-Dong Huang & Peng Cao & Heng-Shan Wang & Jin Wang & Ye Yu, 2024. "Finely ordered intracellular domain harbors an allosteric site to modulate physiopathological function of P2X3 receptors," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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