Faculty, Staff and Student Publications
Publication Date
9-20-2023
Journal
Nature Communications
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.
Keywords
Male, Animals, Guinea Pigs, Mice, Cough, Carcinoma, Renal Cell, Quercetin, Taste, Kidney Neoplasms
DOI
10.1038/s41467-023-41495-0
PMID
37730705
PMCID
PMC10511716
PubMedCentral® Posted Date
9-20-2023
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes