Chronic cough relief by allosteric modulation of P2X3 without taste disturbance.
Chronic cough relief by allosteric modulation of P2X3 without taste disturbance.
复制标题
通过对 P2X3 的异构调节缓解慢性咳嗽，且无味觉干扰。
DOI：
10.1038/s41467-023-41495-0
复制
发表时间：
2023-09-20
影响因子：
16.6
通讯作者：
Yu, Ye
中科院分区：
文献类型：
--
作者：
Guo, Chang-Run;Zhang, Zhong-Zhe;Zhou, Xing;Sun, Meng-Yang;Li, Tian-Tian;Lei, Yun-Tao;Gao, Yu-Hao;Li, Qing-Quan;Yue, Chen-Xi;Gao, Yu;Lin, Yi-Yu;Hao, Cui-Yun;Li, Chang-Zhu;Cao, Peng;Zhu, Michael X.;Rong, Ming-Qiang;Wang, Wen-Hui;Yu, Ye
P2 X受体是感知细胞外ATP的阳离子通道。许多靶向P2 X受体的候选治疗药物已经开始临床试验或获得批准用于治疗难治性慢性咳嗽（RCC）和其他疾病。然而，目前P2 X受体的负变构调节主要限于中央口袋或左鳍状结构域下方的网站。在这里，我们揭示了P2 X3在头部结构域（IP-HD）的内口袋中的变构调节机制，并表明槲皮素和PSFL 2915（我们基于槲皮素优化的NM-亲和P2 X3抑制剂）对雄性小鼠和豚鼠的止咳作用是通过防止P2 X3中IP-HD的变构变化来实现的。虽然在治疗上与新许可的P2 X3 RCC药物吉法匹生相当，但槲皮素和PSFL 2915对味道没有吉法匹生那样的不良影响。因此，通过IP-HD对P2 X3的变构调节可能是缓解RCC的药物策略。P2 X3激活需要在ATP结合后收紧头部结构域的内袋（IP-HD）。在这里，作者证明了用变构小分子靶向IP-HD为无味觉异常的难治性慢性咳嗽的治疗方法的开发提供了一种潜在的策略。
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. P2X3 activation requires tightening the inner pocket of the head domain (IP-HD) following ATP binding. Here the authors demonstrate that targeting the IP-HD with allosteric small molecules presents a potential strategy for the development of therapeutics for refractory chronic cough without taste abnormalities.
登录
查看更多内容
影响因子：
3.7
作者：
Tvrdonova V;Rokic MB;Stojilkovic SS;Zemkova H
通讯作者：
Zemkova H
影响因子：
3.3
作者：
de Rooij, E. D.;von Toussaint, U.;Goedheer, W. J.
通讯作者：
Goedheer, W. J.
影响因子：
2.7
作者：
Ford, Anthony P.;Dillon, Michael P.;Gever, Joel R.
通讯作者：
Gever, Joel R.
影响因子：
15
作者：
Gervasio, FL;Laio, A;Parrinello, M
通讯作者：
Parrinello, M
影响因子：
4.5
作者：
通讯作者：
--