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Druggable site near the upper vestibule determines the high affinity and P2X3 selectivity of Sivopixant, a clinical candidate for refractory chronic cough
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  • Dong-Ping Wang,
  • Meng Zhang,
  • Ming Li,
  • Xiao-Na Yang,
  • Chang-Zhu Li,
  • Peng Cao,
  • Michael Zhu,
  • Yun Tian,
  • Ye Yu,
  • Yun-Tao Lei
Dong-Ping Wang
Hunan Agricultural University
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Meng Zhang
Hunan Agricultural University
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Ming Li
China Pharmaceutical University
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Xiao-Na Yang
Hunan Agricultural University
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Chang-Zhu Li
Hunan Academy of Forestry
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Peng Cao
Nanjing University of Chinese Medicine
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Michael Zhu
The University of Texas Health Science Center at Houston John P and Katherine G McGovern Medical School
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Yun Tian
Hunan Agricultural University
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Ye Yu
Shanghai Jiao Tong University
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Yun-Tao Lei
China Pharmaceutical University School of Science

Corresponding Author:[email protected]

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Abstract

Background and Purpose: The ionotropic purinergic trimeric receptor P2X3 is a new drug target other than the opioid receptor for the treatment of refractory chronic cough (RCC). However, the only marketed P2X3 antagonist, Gefapixant/AF-219, has a side effect of taste disorders due to simultaneous action on the human P2X2/3 (hP2X2/3) heterotrimer. Therefore, selective molecules with high affinity for the hP2X3 homotrimer and low affinity for the hP2X2/3 heterotrimer have potential in iteration 2.0 RCC drug development, such as Sivopixant/S-600918, a clinical phase II RCC candidate with lower taste disturbance than Gefapixant. S-600918 and its analogue (3-(4-((3-chloro-4-isopropoxyphenyl)amino)-3-(4-methylbenzyl)-2,6-dioxo-3,6-dihydro-1,3,5-triazin-1(2H)-yl)propanoic acid (DDTPA) exhibit both high affinity and high selectivity for hP2X3 homotrimers compared to hP2X2/3 heterotrimer. The mechanism of its druggable site and this high selectivity is not clear. Experimental Approach: Here, we reveal a novel allosteric mechanism that distinguishes this drug candidate from other P2X3 inhibitors through chimera construction, site covalent occupation, metadynamics, mutagenesis, and electrophysiology. Key Results: We suggest that the tri-symmetric site adjacent to the upper vestibule determines the high affinity and selectivity of S-600918/DDTPA for hP2X3. Only four amino acids of the hP2X2 upper body domain swapped with hP2X3, allow the hP2X2/3 heterotrimer to gain comparable affinity for S-600918/DDTPA as the hP2X3 homotrimer. Conclusion and Implications: Thus, we have revealed the molecular basis for the cough suppressive effects and reduced side effects of new RCC clinical candidates from the perspective of receptor-ligand recognition, which may provide information critical for the development of new drugs targeting P2X3 for indications such as RCC, idiopathic pulmonary fibrosis (IPF), and primary hypertension.
29 Jan 2023Submitted to British Journal of Pharmacology
31 Jan 2023Submission Checks Completed
31 Jan 2023Assigned to Editor
31 Jan 2023Review(s) Completed, Editorial Evaluation Pending
20 Feb 2023Reviewer(s) Assigned
23 May 2023Editorial Decision: Revise Minor
13 Sep 20231st Revision Received
14 Sep 2023Submission Checks Completed
14 Sep 2023Assigned to Editor
14 Sep 2023Review(s) Completed, Editorial Evaluation Pending
14 Sep 2023Reviewer(s) Assigned
14 Oct 2023Editorial Decision: Accept