Chronic cough relief by allosteric modulation of P2X3 without taste disturbance

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, Michael X. Zhu, Ming-Qiang Rong (), Wen-Hui Wang () and Ye Yu ()
Additional contact information
Chang-Run Guo: 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

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-41495-0

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