Searching new targets for anthelminthic strategies:: Interference with glycosphingolipid biosynthesis and phosphorylcholine metabolism affects development of Caenorhabditis elegans
Searching new targets for anthelminthic strategies:: Interference with glycosphingolipid biosynthesis and phosphorylcholine metabolism affects development of Caenorhabditis elegans
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DOI：
10.1016/j.ijpara.2005.02.015
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发表时间：
2005-07-01
影响因子：
4
通讯作者：
Geyer, R
中科院分区：
文献类型：
--
作者：
Lochnit, G;Bongaarts, R;Geyer, R
线虫感染是人类和动物最常见的疾病之一。它们的特点是死亡率低但发病率高，从而反映了这些寄生虫对其宿主的适应。目前使用的驱虫药的耐药性以及严重的副作用和功效仅限于不同的幼虫阶段或寄生虫，需要紧急开发新的、更具线虫特异性的药物，以寄生虫限制的生物合成途径的酶为目标。秀丽隐杆线虫已被发现是寄生线虫、药物筛选和发育研究的良好模型系统。结构分析揭示了关节系列的线虫特异性鞘糖脂结构，部分带有磷酸胆碱取代基。这些生物分子似乎在线虫的发育、繁殖力和宿主体内的生存中发挥着重要作用，因此是开发新驱虫策略的良好候选目标。在这里，我们展示了针对糖鞘脂生物合成或胆碱代谢酶的 RNAi 实验在一定程度上导致了生育能力的急剧下降。我们进一步测试了这些途径的各种化学抑制剂，发现对线虫的发育有显着影响，导致发育停滞、不育和部分致死。因此，此类抑制剂可以帮助定义新的驱虫药类别。 (c) 2005 年由 Elsevier Ltd 代表澳大利亚寄生虫学协会出版。
Nematode infections are amongst the most abundant diseases of man and animals. They are characterised by a low mortality but high morbidity, thus reflecting the adaptation of these parasites to their hosts. Resistance as well as severe side-effects and efficacies restricted to distinct larval stages or parasites of the anthelmithics used at present require the urgent development of new and more nematode-specific drugs, targeting enzymes of parasite restricted biosynthetic routes. Caenorhabditis elegans has been found to be a good model system for parasitic nematodes, drug screening and developmental studies. Structural analyses have revealed nematode-specific glycosphingolipid structures of the arthro-series, carrying in part, phosphorylcholine substituents. These biomolecules appear to play important roles in nematode development, fertility and survival within the host and are, therefore, good target-candidates for the development of new anthelminthic strategies. Here we show that RNAi experiments targeting enzymes of glycosphingolipid biosynthesis or choline metabolism result, in part, in a drastic reduction of fertility. We further tested various chemical inhibitors of these pathways and found significant effects on the development of the worms, resulting in developmental arrest, sterility and, in part, lethality. Such inhibitors can, therefore, help to define new classes of anthelminthics. (c) 2005 Published by Elsevier Ltd on behalf of Australian Society for Parasitology Inc.