Cyclooctadepsipeptides——一个anthelmintically活跃类化合物表现出一种新颖的方式行动。

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困难,Schmitt-Wrede惠普,Krucken J, Marinovski P, Wunderlich F,威尔逊J, Amliwala K, Holden-Dye L,沃克R

Cyclooctadepsipeptides——一个anthelmintically活跃类化合物表现出一种新颖的方式行动。

Int J Antimicrob代理。2003年9月,22(3):318 - 31所示。

PubMed ID

13678839 (在PubMed

]

文摘

有三个主要驱肠虫剂用于兽医类:苯并咪唑/ prebenzimidazoles, tetrahydropyrimidines / imidazothiazoles,大环内酯。在线虫中,有五个目标,现有的打虫药:nicotinergic乙酰胆碱受体的目标tetrahydropyrimidines / imidazothiazoles和间接的acetylcholineesterase抑制剂;GABA受体哌嗪的目标,glutamate-gated氯通道的目标大环内酯,和beta-tubulin prebenzimidazoles /苯并咪唑的目标。所有这些驱肠虫剂目前在世界范围内的传播严重危险,因为抗线虫的羊、牛、马和猪。类cyclooctadepsipeptides已进入现场的打虫药的研究在1990年代早期。PF1022A,第一个anthelmintically活跃成员,是一个天然化合物的真菌无孢菌类属于山茶的叶子的微生物区系。PF1022A包含4 N-Methyl-L-leucines 2 D-lactic酸和2-D-phenyllactic酸安排作为一个循环octadepsipeptide L-D-L-configuration交替。Emodepside PF1022A的半合成衍生物与吗啉环在每个D-phenyllactic酸在对位。驱虫剂活动是针对胃肠道线虫在鸡,老鼠,老鼠,梅里恩,狗、猫、羊、牛和马。此外,对旋毛虫幼虫在肌肉emodepside活跃,微丝蚴和preadult丝虫属和Dictyocaulus viviparus。 PF1022A and emodepside are fully effective against benzimidazole-, levamisole or ivermectin-resistant nematodes in sheep and cattle. In Ascaris suum both cyclooctadepsipeptides lead to paralysis indicating a neuropharmacological action of these compounds. Using a PF1022A-ligand immunoscreening of a cDNA library from Haemonchus contortus a cDNA clone of 3569 base pairs could be identified. This clone codes for a novel 110 kDa heptahelical transmembrane receptor, named HC110R. Database- and phylogenetic analysis reveals that this receptor is a homolog to B0457.1 from Caenorhabditis elegans and has significant similarity to latrophilins from human, cattle and rat. HC110R is located in the plasma membrane and in lysosomes and endosomes. Alpha-latrotoxin, the poison of the black widow spider, binds at a 54 kDa aminoterminal fragment of HC110R. After binding a Ca2+-influx into HEK293 cells is induced which can be blocked by EGTA, Cd2+ or nifedipin. PF1022A or emodepside also bind to this 54 kDa aminoterminal region of HC110R and interact with the functional responses of alpha-latrotoxin. In C. elegans antibodies against the C-or N-terminus of HC110R bind to the B0457.1 protein located in the pharynx. Electrophysiological studies reveal that emodepside inhibits pharyngeal pumping of the nematodes in a concentration dependent way with an IC(50) value of about 4 nM. Thus, it is tempting to speculate that emodepside exerts its action on nematodes via a latrophilin-like receptor which might have an important regulatory function on pharyngeal pumping.

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药物

Emodepside