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首页> 外文OA文献 >Monepantel irreversibly binds to and opens Haemonchus contortus MPTL-1 and Caenorhabditis elegans ACR-20 receptors.
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Monepantel irreversibly binds to and opens Haemonchus contortus MPTL-1 and Caenorhabditis elegans ACR-20 receptors.

机译：Monepantel不可逆地结合并打开扭旋Haemonchus contortus MPTL-1和秀丽隐杆线虫ACR-20受体。

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摘要

Monepantel is a recently developed anthelmintic with a novel mode of action. Parasitic nematodes with reduced sensitivity to monepantel have led to the identification of MPTL-1, a ligand-gated ion-channel subunit of the parasitic nematode Haemonchus contortus, as a potential drug target. Homomeric MPTL-1 channels reconstituted in Xenopus oocytes are gated by µM concentrations of betaine and mM concentrations of choline. Measurement of reversal potentials indicated that the channel has a similar conductance for Na(+) and K(+) ions and does not permeate Ca(2+). Concentrations of monepantel (amino-acetonitrile derivative [AAD]-2225) >0.1 μM, but not its inactive enantiomer AAD-2224, induced channel opening in an irreversible manner. Currents elicited by monepantel alone were larger than the maximal current amplitudes achieved with betaine or choline, making monepantel a superagonist. Currents elicited by betaine or choline were allosterically potentiated by nM concentrations of monepantel and to a much smaller degree by AAD-2224. We have also reconstituted the Caenorhabditis elegans homomeric ACR-20 receptor in Xenopus oocytes. The acr-20 sequence has higher similarity to mptl-1 than acr-23, the primary target for monepantel mode of action in C. elegans. The ACR-20 channel is gated similarly as MPTL-1. Monepantel, but not AAD-2224, was able to induce channel opening in an irreversible manner at similar concentrations as for MPTL-1. Interestingly, the allosteric potentiation measured in the presence of betaine was much smaller than in MPTL-1 receptors. Together, these results establish the mode of action of monepantel in H. contortus and contribute to our understanding of the mode of action of this anthelmintic.
机译：Monepantel是一种新型驱虫药，具有新颖的作用方式。对monepantel敏感性降低的寄生线虫导致了MPTL-1的鉴定，它是潜在的药物靶点，是寄生线虫Haemonchus contortus的配体门离子通道亚单位。在非洲爪蟾卵母细胞中重组的同质MPTL-1通道被µM浓度的甜菜碱和mM浓度的胆碱控制。反向电位的测量表明，该通道对Na（+）和K（+）离子具有相似的电导率，并且不会渗透Ca（2+）。 monepantel（氨基乙腈衍生物[AAD] -2225）的浓度> 0.1μM，但不失活对映体AAD-2224，却以不可逆的方式诱导了通道的开放。单独由monepantel引发的电流大于甜菜碱或胆碱所达到的最大电流幅度，从而使monepantel成为超激动剂。甜菜碱或胆碱引起的电流被nM浓度的monepantel变构增强，而AAD-2224则变小得多。我们还在非洲爪蟾卵母细胞中重组了秀丽隐杆线虫同源ACR-20受体。 acr-20序列与mptl-1的相似性高于acr-23（秀丽隐杆线虫的monepantel作用方式的主要靶标）。 ACR-20通道的门控类似于MPTL-1。 Monepantel而非AAD-2224能够以与MPTL-1相似的浓度以不可逆的方式诱导通道开放。有趣的是，在甜菜碱存在下测得的变构电位比在MPTL-1受体中小得多。在一起，这些结果建立了莫尼潘特尔在捻转血吸虫中的作用方式，并有助于我们对这种驱虫药的作用方式的理解。

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