Monepantel Irreversibly Binds to and Opens Haemonchus contortus MPTL-1 and Caenorhabditis elegans ACR-20 Receptors
Monepantel Irreversibly Binds to and Opens Haemonchus contortus MPTL-1 and Caenorhabditis elegans ACR-20 Receptors
复制标题
DOI：
10.1124/mol.114.095653
复制
发表时间：
2015-01-01
影响因子：
3.6
通讯作者：
Rufener, Lucien
中科院分区：
文献类型：
--
作者：
Baur, Roland;Beech, Robin;Rufener, Lucien
莫奈太尔是一种新近开发的作用机制新颖的驱虫药。对莫尼泮的敏感性降低的寄生线虫导致了MPTL-1（寄生线虫捻转血矛线虫的配体门控离子通道亚基）作为潜在药物靶标的鉴定。同源MPTL-1通道重建爪蟾卵母细胞门控μ M浓度的甜菜碱和胆碱的mM浓度。反向电位的测量表明，该通道具有类似的电导Na+和K+离子和不渗透Ca 2+。莫奈太尔（氨基乙腈衍生物[ AAD]-2225）的浓度>0.1 μ M，但其无活性对映体AAD-2224不诱导通道以不可逆方式开放。单用莫奈太尔引起的电流大于用甜菜碱或胆碱达到的最大电流幅度，使莫奈太尔成为超激动剂。由甜菜碱或胆碱引起的电流被莫奈太尔的nM浓度变构增强，AAD-2224的作用程度要小得多。我们还重建了秀丽隐杆线虫同源ACR-20受体在爪蟾卵母细胞。acr-20序列与mptl-1的相似性高于acr-23，acr-23是莫奈太尔在C.优雅ACR-20通道的门控与MPTL-1类似。Monepantel（但不是AAD-2224）能够在与MPTL-1相似的浓度下以不可逆的方式诱导通道开放。有趣的是，在甜菜碱的存在下测量的变构增强比在MPTL-1受体中小得多。总之，这些结果确立了莫奈太尔在H.扭曲，有助于我们了解这种驱虫剂的作用方式。
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 mu M 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 Ca2+. Concentrations of monepantel (amino-acetonitrile derivative [ AAD]-2225)>0.1 mu M, 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.