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The narrow-spectrum anthelmintic oxantel is a potent agonist of a novel acetylcholine receptor subtype in whipworms
bioRxiv - Pharmacology and Toxicology Pub Date : 2020-09-17 , DOI: 10.1101/2020.09.17.301192
Tina V. A. Hansen , Susanna Cirera , Cédric Neveu , Kirstine Calloe , Dan A. Klaerke , Richard J Martin

In the absence of efficient alternative strategies, the control of parasitic nematodes, impacting human and animal health, mainly relies on the use of broad-spectrum anthelmintic compounds. Unfortunately, most of these drugs have a limited single-dose efficacy against infections caused by the whipworm, Trichuris. These infections are of both human and veterinarian importance. However, in contrast to a wide range of parasitic nematode species, the narrow-spectrum anthelmintic oxantel has a high efficacy on Trichuris spp. Despite this knowledge, the molecular target(s) of oxantel within Trichuris is still unknown. In the distantly related pig roundworm, Ascaris suum, oxantel has a small, but significant effect on the recombinant homomeric Nicotine-sensitive ionotropic acetylcholine receptor (N-AChR) made up of five ACR-16 subunits. Therefore, we hypothesized that in whipworms, a putative homolog of an ACR-16 subunit, can form a functional oxantel-sensitive receptor. Using the pig whipworm T. suis as a model, we identified and cloned a novel ACR-16-like receptor subunit and successfully expressed the corresponding homomeric channel in Xenopus laevis oocytes. Electrophysiological experiments revealed this receptor to have distinctive pharmacological properties with oxantel acting as a full agonist, hence we refer to the receptor as an O-AChR subtype. Pyrantel activated this novel O-AChR subtype moderately, whereas classic nicotinic agonists surprisingly resulted in only minor responses. We demonstrated that the novel Tsu-ACR-16-like receptor is indeed a target for oxantel and is more responsive to oxantel than the ACR-16 receptor from A. suum. These finding most likely explain the high sensitivity of whipworms to oxantel, and highlights the importance of the discovery of additional distinct receptor subunit types within Trichuris that can be used as valuable screening tools to evaluate the effect of new synthetic or natural anthelmintic compounds.

中文翻译:

窄谱驱虫草黄嘌呤是鞭虫中新型乙酰胆碱受体亚型的有效激动剂。

在缺乏有效的替代策略的情况下,对寄生虫线虫的控制会影响人和动物的健康,主要依靠使用广谱驱虫剂。不幸的是,大多数这些药物对鞭虫Trichuris引起的感染的单剂量功效有限。这些感染具有人类和兽医的重要性。然而,与多种寄生线虫种类相比,窄谱驱虫性黄嘌呤对Trichuris spp具有很高的功效。尽管有这些知识,Trichuris中黄嘌呤的分子靶标仍是未知的。在远缘相关的猪round虫中猪A虫,oxantel对重组同源一个小的,但是显著效果Ñ icotine敏感离子型乙酰胆碱受体(Ñ五个ACR-16亚单位组成-AChR)。因此,我们假设在鞭虫中,ACR-16亚基的推定同源物可以形成功能性的对黄嘌呤敏感的受体。使用猪鞭虫T. suis作为模型,我们鉴定并克隆了一个新的ACR-16样受体亚基,并成功在非洲爪蟾卵母细胞中表达了相应的同源通道。电生理实验表明,该受体具有独特的药理学特性,其中黄嘌呤是完全的激动剂,因此我们将该受体称为O-AChR亚型。Pyrantel适度激活了这种新型O -AChR亚型,而经典的烟碱激动剂令人惊讶地仅产生了轻微反应。我们证明了小说Tsu- ACR-16样受体确实是oxantel的目标并且更加适应oxantel比从ACR-16受体A.猪蛔虫。这些发现最有可能解释了鞭虫对黄嘌呤的高度敏感性,并突出了在Trichuris中发现其他不同受体亚基类型的重要性,这些亚基可以用作有价值的筛选工具,以评估新的合成或天然驱虫化合物的效果。
更新日期:2020-09-20
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