筛选草药和天然产品库,帮助发现新型人类 P2X7 异构调节剂。

IF 3 4区 医学 Q2 NEUROSCIENCES Purinergic Signalling Pub Date : 2024-10-22 DOI:10.1007/s11302-024-10055-6
Stefan Bidula, Waraporn Piyasirananda, Hanna Bielecka, Lučka Bibič, Andrew Beekman, Leanne Stokes
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引用次数: 0

摘要

由于 P2X7 在炎症信号传导中的作用,它已成为多种疾病的新兴治疗靶点。本研究旨在利用传统医学中使用的植物的独特化学库,从天然来源中发现新型异构调节剂。我们从 NCI 天然产物库中发现了几种 P2X7 拮抗剂化合物,包括 confertifolin 和 digallic acid(IC50 值分别为 3.86 µM 和 4.05 µM)。我们还发现莨菪亭是一种新型的 hP2X7 正异构调节剂。通过筛选传统药用植物提取物库,我们发现 39 种植物对 hP2X7 具有抑制作用,17 种植物具有正异构调节剂活性。我们利用计算对接技术从这些植物物种中筛选出确定的成分并确定潜在的拮抗剂,研究了九种纯化的化学物质,包括黄酮类化合物槲皮素、山柰酚、ECG 和 EGCG。结果表明,这些物质能抑制 ATP 诱导的 HEK-hP2X7 细胞对 YO-PRO-1 的摄取;不过,我们还发现,使用无细胞 DNA YO-PRO-1 荧光测试法,所有四种黄酮类化合物都表现出明显的检测干扰。在 ATP 诱导的 YO-PRO-1 摄取试验和全细胞膜片钳记录中,我们研究了一种具有积极调节活性的植物提取物薯蓣皂苷,并确定薯蓣皂苷具有 PAM 活性。然而,在应用 > 10 分钟后观察到膜渗透,这限制了 dioscin 作为药理学工具的应用。这项研究介绍了一种有用的工作流程,它采用多种检测方法来鉴定新型的人类 P2X7 异位调节剂。
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Screening herbal and natural product libraries to aid discovery of novel allosteric modulators of human P2X7.

 P2X7 is an emerging therapeutic target for several disorders and diseases due to its role in inflammatory signalling. This study aimed to exploit the unique chemical libraries of plants used in traditional medicinal practices to discover novel allosteric modulators from natural sources. We identified several compounds from the NCI Natural Product library as P2X7 antagonists including confertifolin and digallic acid (IC50 values 3.86 µM and 4.05 µM). We also identified scopafungin as a novel positive allosteric modulator of hP2X7. Screening a traditional medicinal plant extract library revealed 39 plant species with inhibitory action at hP2X7 and 17 plant species with positive allosteric modulator activity. Using computational docking to filter identified components from these plant species and determine potential antagonists, we investigated nine purified chemicals including flavonoids quercetin, kaempferol, ECG, and EGCG. These were shown to inhibit ATP-induced YO-PRO-1 uptake into HEK-hP2X7 cells; however, we also showed that all four flavonoids demonstrated significant assay interference using a cell-free DNA YO-PRO-1 fluorescence test. One plant extract, Dioscorea nipponica, demonstrating positive modulator activity was investigated, and dioscin was identified as a glycoside with PAM activity in ATP-induced YO-PRO-1 uptake assay and whole-cell patch-clamp recordings. However, membrane permeabilisation was observed following application > 10 min limiting the use of dioscin as a pharmacological tool. This work describes a useful workflow with multiple assays for the identification of novel allosteric modulators for human P2X7.

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来源期刊
Purinergic Signalling
Purinergic Signalling 医学-神经科学
CiteScore
6.60
自引率
17.10%
发文量
75
审稿时长
6-12 weeks
期刊介绍: Nucleotides and nucleosides are primitive biological molecules that were utilized early in evolution both as intracellular energy sources and as extracellular signalling molecules. ATP was first identified as a neurotransmitter and later as a co-transmitter with all the established neurotransmitters in both peripheral and central nervous systems. Four subtypes of P1 (adenosine) receptors, 7 subtypes of P2X ion channel receptors and 8 subtypes of P2Y G protein-coupled receptors have currently been identified. Since P2 receptors were first cloned in the early 1990’s, there is clear evidence for the widespread distribution of both P1 and P2 receptor subtypes in neuronal and non-neuronal cells, including glial, immune, bone, muscle, endothelial, epithelial and endocrine cells.
期刊最新文献
Correction to: Preparation and preliminary evaluation of a tritium-labeled allosteric P2X4 receptor antagonist. Machine learning-aided search for ligands of P2Y6 and other P2Y receptors. Purinergic regulation of pulmonary vascular tone. Role of ecto-5'-nucleotidase in bladder function activity and smooth muscle contractility. Unexpected role of microglia and P2Y12 in the induction of and emergence from anesthesia.
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