The narrow-spectrum anthelmintic oxantel is a potent agonist of a novel acetylcholine receptor subtype in whipworms.
The narrow-spectrum anthelmintic oxantel is a potent agonist of a novel acetylcholine receptor subtype in whipworms.
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DOI：
10.1371/journal.ppat.1008982
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发表时间：
2021-03
期刊：
影响因子：
6.7
通讯作者：
Martin RJ
中科院分区：
文献类型：
--
作者：
Hansen TVA;Cirera S;Neveu C;Courtot E;Charvet CL;Calloe K;Klaerke DA;Martin RJ
在缺乏有效替代策略的情况下，控制影响人类和动物健康的寄生线虫主要依赖于使用广谱驱虫化合物。不幸的是，这些药物中的大多数对鞭虫鞭虫引起的感染具有有限的单剂量功效。这些感染对人类和兽医都很重要。然而，与广泛的寄生线虫物种相反，窄谱驱虫剂oxantel对鞭虫属具有高效力。尽管有这些知识，但鞭虫体内奥生特尔的分子靶点仍然未知。在远亲猪蛔虫中，oxantel对由5个ACR-16亚基组成的重组同型烟碱敏感型离子型乙酰胆碱受体（N-AChR）具有较小但显著的影响。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oxantel敏感受体。利用猪鞭虫T.以猪为模型，我们鉴定并克隆了一个新的ACR-16样亚基，并在非洲爪蟾卵母细胞中成功表达了相应的同源通道。电生理学实验表明，该受体具有独特的药理学特性，oxantel作为一个完整的激动剂，因此我们将该受体称为O-AChR亚型。噻嘧啶中度激活这种新型O-AChR亚型，而经典烟碱激动剂令人惊讶地仅导致轻微反应。我们观察到，ACR-16样亚基在自由生活的线虫秀丽隐杆线虫中的表达赋予了重组蠕虫对oxantel的敏感性增加。我们证明了新的Tsu-ACR-16样受体确实是oxantel的靶点，尽管可能涉及其他受体。这些发现为鞭虫对oxantel的高敏感性的理解带来了新的见解，并强调了发现鞭虫内其他不同受体亚基类型的重要性，这些受体亚基类型可用作筛选工具来评估新的合成或天然驱虫化合物的效果。鞭虫（Trichuris trichiura）是一种肠道寄生线虫，全球约有2.896亿人感染，主要是发展中国家的儿童。慢性T.鞭毛虫感染可导致痢疾、生长迟缓和认知能力下降。众所周知，鞭虫感染很难用大多数可用的驱虫药控制，包括那些常用于大规模药物管理计划的驱虫药。最近的随机对照试验与鞭虫感染的人，报告了上级疗效的oxantel，一个经典的，窄谱驱虫剂，开发用于治疗鞭虫感染。尽管有这些知识，但尚未鉴定出鞭虫中oxantel的分子靶标。在这项研究中，我们使用了从猪鞭虫作为模型，并确定了受体，这是探索使用爪蟾卵母细胞表达系统。我们证明，这种受体是高度响应于oxantel，因此在鞭虫oxantel的主要目标。此外，我们发现这种受体类型是独特的，只存在于古老的寄生线虫群，分支I，其中还包括重要的人畜共患寄生虫旋毛虫。我们的研究结果解释了oxantel的特定作用模式，并为其他医学或兽医学重要寄生线虫进化枝I中类似受体亚型的额外表征开辟了道路。
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 veterinary 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 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 observed that the expression of the ACR-16-like subunit in the free-living nematode Caenorhabditis elegans conferred an increased sensitivity to oxantel of recombinant worms. We demonstrated that the novel Tsu-ACR-16-like receptor is indeed a target for oxantel, although other receptors may be involved. These finding brings new insight into the understanding of 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 screening tools to evaluate the effect of new synthetic or natural anthelmintic compounds. The human whipworm, Trichuris trichiura, is an intestinal parasitic nematode infecting approximately 289.6 million people globally, primarily children living in developing countries. Chronic T. trichiura infection may cause dysentery, growth stunting and decreased cognitive performance. Whipworm infections are notoriously difficult to control with most available anthelmintics, including those commonly used in mass drug administration programs. Recent randomised controlled trials with whipworm-infected humans, have reported superior efficacies of oxantel, a classic, narrow-spectrum anthelmintic, developed for the treatment of Trichuris infections. Despite this knowledge, the molecular target(s) of oxantel within the whipworm has not been identified. In this study, we used the whipworm from pigs as a model and identified a receptor, which was explored using the Xenopus oocyte expression system. We demonstrated that this receptor is highly responsive to oxantel, and therefore a major target of oxantel within Trichuris. In addition, we discovered that this receptor-type is distinctive and only present in the ancient group of parasitic nematodes, Clade I, which also includes the important zoonotic parasite Trichinella. Our findings, explain the specific mode of action of oxantel and open the way for additional characterization of similar receptor subtypes in other medically or veterinary important parasitic nematodes of Clade I.
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DOI：
10.1016/j.ijpddr.2017.11.002
发表时间：
2017-12
期刊：
International journal for parasitology. Drugs and drug resistance
影响因子：
--
作者：
Hansen TVA;Williams AR;Denwood M;Nejsum P;Thamsborg SM;Friis C
通讯作者：
Friis C
影响因子：
2.4
作者：
DALE, VME;MARTIN, RJ
通讯作者：
MARTIN, RJ
影响因子：
3.8
作者：
Duguet, Thomas B.;Charvet, Claude L.;Beech, Robin N.
通讯作者：
Beech, Robin N.
影响因子：
3.8
作者：
Diawara A;Halpenny CM;Churcher TS;Mwandawiro C;Kihara J;Kaplan RM;Streit TG;Idaghdour Y;Scott ME;Basáñez MG;Prichard RK
通讯作者：
Prichard RK
哺乳动物烟碱乙酰胆碱受体：从结构到功能。
影响因子：
33.6
作者：
Albuquerque EX;Pereira EF;Alkondon M;Rogers SW
通讯作者：
Rogers SW