2. Academic Validation
  3. Chronic cough relief by allosteric modulation of P2X3 without taste disturbance

Chronic cough relief by allosteric modulation of P2X3 without taste disturbance

  • Nat Commun. 2023 Sep 20;14(1):5844. doi: 10.1038/s41467-023-41495-0.
Chang-Run Guo # 1 2 3,  Zhong-Zhe Zhang # 1,  Xing Zhou # 1,  Meng-Yang Sun 1,  Tian-Tian Li 1,  Yun-Tao Lei 1,  Yu-Hao Gao 1,  Qing-Quan Li 1,  Chen-Xi Yue 1,  Yu Gao 1,  Yi-Yu Lin 1,  Cui-Yun Hao 1,  Chang-Zhu Li 4,  Peng Cao 5,  Michael X Zhu 6,  Ming-Qiang Rong 7,  Wen-Hui Wang 8,  Ye Yu 9 10
Affiliations

Affiliations

  • 1 School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China.
  • 2 School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, China.
  • 3 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, China.
  • 4 State Key Laboratory of Utilization of Woody Oil Resource, Hunan Academy of Forestry, Changsha, Hunan, 410004, China.
  • 5 Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
  • 6 Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas, 77030, USA.
  • 7 The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, China. rongmq@hunnu.edu.cn.
  • 8 School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China. whwang@cpu.edu.cn.
  • 9 School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China. yuye@cpu.edu.cn.
  • 10 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, China. yuye@cpu.edu.cn.
  • # Contributed equally.
PMID: 37730705 DOI: 10.1038/s41467-023-41495-0
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.

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