The matrix associated astacin enzymes: novel targets in the control of key GI nematodes of ruminants.

寄生线虫是人类及其家畜的重要病原体，可引起慢性衰弱性疾病。毛圆线虫是放牧牲畜中广泛存在的具有重要经济意义的病原体，在世界范围内普遍存在。感染阶段发生在牧场，致病性阶段发生在胃肠道。这些寄生虫在英国很常见，据估计，它们每年给养羊业造成的损失超过8400万英镑。报告的暴发次数和这些寄生虫的地理范围正在增加，气候日益温暖和潮湿延长了自由生活阶段的生存时间是一个促成因素。可用于控制这些感染的药物数量有限，由于过度使用而产生耐药性是司空见惯的。现在还报告了对不同类别药物的多重耐药，迫切需要开发新的药物类别。所有的线虫都被一种叫做角质层的坚硬的外骨骼所保护，角质层是一种通过蜕皮过程反复脱落和重新合成的基质。表皮结构和蜕皮过程是线虫特有的，我们将针对参与该结构的构建和脱落的关键酶。我们使用了一个叫做秀丽隐杆线虫的实验室模型系统来研究这种结构，我们已经确定了与寄生线虫共享的关键酶。我们现在建议在感染绵羊的重要线虫物种中研究这些酶，并将结合结构生物学、遗传学和生物化学来验证这些靶点。通过与药物发现专家合作，我们将确定对这些酶有效的小分子，并与兽医寄生虫学专家合作，我们将在寄生虫本身中测试化合物。这项工作将为开发控制这些具有重要经济意义的寄生虫的新药奠定重要基础，预计这些化合物将对牛、家畜和人的更广泛的感染性线虫寄生虫有效。

The parasitic nematodes are important pathogens of man and his domestic animals that cause chronic debilitating diseases. The trichostrongylid nematodes represent widespread and economically important pathogens of grazing livestock and have a worldwide prevalence. The infective stages are taken up on pasture and pathogenic stages are found in the gastro-intestinal tract. These parasites are common throughout the United Kingdom and they are estimated to cost the sheep farming industry in excess of £84 million per annum. The numbers of reported outbreaks and the geographic range of these parasites are increasing, with an increasingly warmer and wetter climate prolonging the survival of the free-living stages being a contributing factor. A limited number of drugs are available to control these infections with resistance being commonplace due to their over-application. Multiple resistance to different classes of drugs has now also been reported and there is an urgent requirement to develop new classes of drugs. All nematodes are protected by a tough exoskeleton called the cuticle, a matrix that is shed and re-synthesised repeatedly through a process called moulting. The cuticle structure and the moulting process are specific to nematodes and we will target key enzymes that are involved in the construction and shedding of this structure. We have used a laboratory model system called Caenorhabditis elegans to study this structure and we have identified the key enzymes that are shared with the parasitic nematodes. We now propose to study these enzymes in the important nematode species that infect sheep and will use a combination of structural biology, genetics and biochemistry to validate these targets. In collaboration with experts in drug discovery we will identify small molecules that are effective against these enzymes and in collaboration with experts in veterinary parasitology we will test the compounds in the parasites themselves. This work will lay the important groundwork in developing new drugs to control these economically important parasites and it is envisaged that these compounds will be effective against a wider range of infective nematode parasites of cattle, domestic animals and man.