P2X3-selective mechanism of Gefapixant, a drug candidate for the treatment of refractory chronic cough.
P2X3-selective mechanism of Gefapixant, a drug candidate for the treatment of refractory chronic cough.
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治疗难治性慢性咳嗽的候选药物 Gefapixant 的 P2X3-选择性机制
DOI：
10.1016/j.csbj.2022.03.030
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发表时间：
2022
影响因子：
6
通讯作者：
中科院分区：
文献类型：
--
作者：
Gefapixant/AF-219选择性作用于P2X3受体的机制尚不清楚。AF-219在P2X3的负变构部位也是其他P2X亚型的一个有效的变构部位。AF-219对P2X3的选择性取决于结合部位的可及性和口袋的内部形状。这一发现将为治疗肾癌等由P2X3介导的疾病的药物设计提供新的视角。Gefapixant/AF-219是一种选择性的P2X3受体抑制剂，是近60年来除右美沙芬外第一个被批准用于治疗难治性慢性咳嗽(RCC)的新药。到目前为止，已经克隆了7种由细胞外ATP激活的P2X亚型(P2X1-7)，而P2X抑制剂的亚型选择性是减少副作用的前提。我们先前已经确定了Gefapixant/AF-219在P2X3受体上的作用部位和作用机制，该受体占据了一个由左鳍状突(LF)和下体(LB)结构域组成的口袋。然而，AF-219选择性作用于P2X3受体的机制尚不清楚。在这里，我们将突变、嵌合体构建、分子模拟、共价占据和化学合成相结合，发现AF-219在P2X3的负变构位点也存在于其他P2X亚型中，至少在P2X1、P2X2和P2X4中是存在的。通过构建AF-219敏感的P2X3和不敏感的P2X2亚型的每个嵌合体，使不敏感的P2X2亚型具有AF-219和AF-353的抑制特性，AF-353是AF-219的类似物，具有更高的亲和力。我们的结果表明，AF-219/AF-353对P2X3的选择性高于其他P2X亚型，这是由P2X3结合位点的可及性和这个口袋的内部形状共同决定的，这一发现可能为治疗肾癌、特发性肺间质纤维化、高血压和膀胱过度活动症等P2X3介导的疾病的药物设计提供新的视角。
The mechanism by which Gefapixant/AF-219 selectively acts on the P2X3 receptor is unclear. The negative allosteric site of AF-219 at P2X3 is also a potent allosteric site for other P2X subtypes. The selectivity of AF-219 for P2X3 is determined by the accessibility of binding site and the internal shape of this pocket. The finding will provide new perspectives for drug design against P2X3-mediated diseases such as RCC. Gefapixant/AF-219, a selective inhibitor of the P2X3 receptor, is the first new drug other than dextromethorphan to be approved for the treatment of refractory chronic cough (RCC) in nearly 60 years. To date, seven P2X subtypes (P2X1-7) activated by extracellular ATP have been cloned, and subtype selectivity of P2X inhibitors is a prerequisite for reducing side effects. We previously identified the site and mechanism of action of Gefapixant/AF-219 on the P2X3 receptor, which occupies a pocket consisting of the left flipper (LF) and lower body (LB) domains. However, the mechanism by which AF-219 selectively acts on the P2X3 receptor is unknown. Here, we combined mutagenesis, chimera construction, molecular simulations, covalent occupation and chemical synthesis, and find that the negative allosteric site of AF-219 at P2X3 is also present in other P2X subtypes, at least for P2X1, P2X2 and P2X4. By constructing each chimera of AF-219 sensitive P2X3 and insensitive P2X2 subtypes, the insensitive P2X2 subtype was made to acquire the inhibitory properties of AF-219 and AF-353, an analog of AF-219 with higher affinity. Our results suggest that the selectivity of AF-219/AF-353 for P2X3 over the other P2X subtypes is determined by a combination of the accessibility of P2X3 binding site and the internal shape of this pocket, a finding that could provide new perspectives for drug design against P2X3-mediated diseases such as RCC, idiopathic pulmonary fibrosis, hypertension and overactive bladder disorder.
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DOI：
10.1007/978-1-4939-9752-7_15
发表时间：
2019-01-01
期刊：
DOCKING SCREENS FOR DRUG DISCOVERY
影响因子：
--
作者：
Bitencourt-Ferreira, Gabriela;de Azevedo, Walter Filgueira, Jr.
通讯作者：
de Azevedo, Walter Filgueira, Jr.
影响因子：
5.6
作者：
Burnstock G
通讯作者：
Burnstock G
影响因子：
5.8
作者：
Larkin, M. A.;Blackshields, G.;Higgins, D. G.
通讯作者：
Higgins, D. G.
影响因子：
2.7
作者：
Brotherton-Pleiss, Christine E.;Dillon, Michael P.;Zhai, Yansheng
通讯作者：
Zhai, Yansheng
影响因子：
64.8
作者：
Hattori, Motoyuki;Gouaux, Eric
通讯作者：
Gouaux, Eric