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，可引起慢性衰弱疾病。毛圆线虫是放牧牲畜广泛存在的重要经济病原体，在世界范围内流行。感染阶段发生在牧场，致病阶段发生在胃肠道。这些寄生虫在整个联合王国很常见，据估计，它们每年给养羊业造成的损失超过8400万GB。报告的疫情数量和这些寄生虫的地理范围正在增加，越来越温暖和潮湿的气候延长了自由生活阶段的生存时间，这是一个促成因素。可用于控制这些感染的药物数量有限，由于过度使用，耐药性很常见。现在也报告了对不同类别药物的多重耐药性，迫切需要开发新类别的药物。所有线虫都受到一种名为角质层的坚韧外骨骼的保护，角质层是一种基质，通过一种名为蜕皮的过程反复脱落并重新合成。角质层的结构和蜕皮过程是线虫特有的，我们将针对参与这一结构的构建和脱落的关键酶。我们使用了一个名为秀丽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。我们现在建议研究感染绵羊的重要线虫物种中的这些酶，并将使用结构生物学、遗传学和生物化学的组合来验证这些目标。我们将与药物研发专家合作，确定对这些酶有效的小分子，并与兽医寄生虫学专家合作，测试寄生虫本身中的化合物。这项工作将为开发控制这些经济上重要的寄生虫的新药奠定重要的基础，预计这些化合物将对更广泛的牛、家畜和人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.