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

基质相关的虾红素酶：控制反刍动物关键胃肠道线虫的新靶点。

基本信息

批准号：
BB/I012885/1
负责人：
Malcolm Walkinshaw
金额：
$ 8.89万
依托单位：
University of Edinburgh
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2012
资助国家：
英国
起止时间：
2012 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FI012885%2F1
关键词：
matrix associated astacin enzymes novel

项目摘要

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.

寄生线虫是人类和家畜的重要病原体，可引起慢性衰弱性疾病。线虫是放牧家畜的重要病原体，在世界范围内普遍存在。感染阶段在牧场进行，致病阶段在胃肠道进行。这些寄生虫在英国各地很常见，估计每年给绵羊养殖业造成的损失超过8400万英镑。报告的疫情数量和这些寄生虫的地理范围正在增加，气候越来越温暖和潮湿，延长了自由生活阶段的生存时间，这是一个促成因素。有限数量的药物可用于控制这些感染，由于过度应用，耐药性很常见。现在还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。所有的线虫都受到一种叫做角质层的坚韧外骨骼的保护，角质层是一种通过蜕皮过程反复脱落和重新合成的基质。角质层结构和蜕皮过程是线虫特有的，我们将针对参与这种结构的构建和脱落的关键酶。我们已经使用了一个实验室模型系统称为秀丽隐杆线虫研究这种结构，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。我们将与药物发现专家合作，确定对这些酶有效的小分子，并与兽医寄生虫学专家合作，我们将测试寄生虫本身的化合物。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，预计这些化合物将有效对抗牛、家畜和人的更广泛的感染性线虫寄生虫。