C. elegans as a tool to discover new anthelmintics.

线虫作为发现新驱虫药的工具。

• 批准号: RGPIN-2015-04129
• 负责人: Moerman, Donald
• 金额: $ 2.48万
• 依托单位: University of British Columbia
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=659940
• 关键词: C.; elegans; tool; discover; new

As pointed out by the World Health Organization (WHO) "Helminth infections impose a great burden on poor populations in the developing world." According to a report by WHO, approximately 2 billion humans have nematode infections worldwide. Nematodes are also serious parasites of livestock and plants and cost billions of dollars a year in crop damage and loss of livestock. Ivermectin is currently the drug of choice to treat nematode infections. Unfortunately, but not unexpectedly, resistance to anthelmintic drugs in general and ivermectin in particular is growing worldwide. These reports of ivermectin resistance are cause for concern and have many organizations calling for the development of new drugs to treat nematode infections.***We believe the non-infectious nematode C. elegans can be used as an efficient surrogate for infectious nematodes. The ease of handling of C. elegans in a laboratory environment make it ideal for drug screening and discovery. We have developed a high throughput screening system that will allow us to explore a wide sampling of the chemical landscape for potential nematicides. Chemicals effective on nematodes may be rare, but if we can sample many chemicals easily we have a reasonable chance of identifying new nematicides. This ease and pace of primary screening in tis nematode should lead to identification of new lead chemicals to be developed as nematicides.***In a pilot study with a known set of 3,000 FDA approved drugs we identified over 95% of the known nematicides. While the screen is still in progress we already have identified several candidate compounds. None of these compounds have previously been shown to affect nematodes and indeed there is little known about any of the compounds. From the perspective of an anthelmintic we are primarily interested in doing further research on compounds with effects limited to nematodes. Part of our filtering was directed at looking for new chemical backbone's as they may be the most likely to affect biochemical pathways in the nematode that have not yet been exploited. We believe this is a promising approach for developing new anthelmintic drugs.***To identify affected pathways for these compounds and possible modes of resistance we will select for drug-resistant animals after mutagenesis and then identify the affected loci. While this has been a time-honored approach used in C. elegans to identify genes involved in drug resistance, determining the molecular identity of affected loci can be a bottleneck. We have developed a multiplex sequencing protocol to identify resistant genes quite easily and it will be applied to resistant strains derived from this project. Longer-term goals will be to work with parasitology labs to see that these drugs get tested on their intended target organisms. If successful we hope to move these compounds into manufacture and testing to help alleviate anthelmintic infections worldwide. **

正如世界卫生组织（世卫组织）指出的那样，“蠕虫感染给发展中国家的贫困人口带来了巨大负担。“根据世卫组织的一份报告，全世界约有20亿人感染线虫。线虫也是牲畜和植物的严重寄生虫，每年造成数十亿美元的作物损失和牲畜损失。 伊维菌素是目前治疗线虫感染的首选药物。不幸的是，但并非出乎意料的是，对一般驱虫药，特别是伊维菌素的耐药性正在全球范围内增长。这些伊维菌素耐药性的报告令人担忧，许多组织呼吁开发治疗线虫感染的新药。我们认为非传染性线虫C.秀丽线虫可用作感染性线虫的有效替代物。C.实验室环境中的秀丽线虫使其成为药物筛选和发现的理想选择。我们已经开发了一个高通量筛选系统，这将使我们能够探索潜在的杀线虫剂的化学景观的广泛采样。对线虫有效的化学物质可能很罕见，但如果我们可以很容易地对许多化学物质进行采样，我们就有合理的机会识别新的杀线虫剂。这种在线虫中进行初步筛选的容易程度和速度应有助于确定新的可开发为杀线虫剂的铅化学品。在一项对已知的3,000种FDA批准的药物进行的试点研究中，我们确定了超过95%的已知杀线虫剂。虽然筛选仍在进行中，但我们已经确定了几种候选化合物。这些化合物以前都没有被证明会影响线虫，实际上对这些化合物知之甚少。从驱虫剂的角度来看，我们主要有兴趣做进一步的研究化合物的效果仅限于线虫。我们的部分过滤是针对寻找新的化学骨架，因为它们可能是最有可能影响尚未被利用的线虫中的生化途径的。我们相信这是一种很有前途的方法，用于开发新的驱虫药物。为了鉴定这些化合物的受影响途径和可能的耐药模式，我们将在诱变后选择耐药动物，然后鉴定受影响的基因座。虽然这是C语言中使用的一种由来已久的方法。为了鉴定与耐药性有关的基因，确定受影响位点的分子身份可能是一个瓶颈。我们已经开发了一种多重测序方案，以确定耐药基因相当容易，它将被应用于耐药菌株来自这个项目。长期目标将是与寄生虫学实验室合作，确保这些药物在预期的目标生物体上进行测试。如果成功，我们希望将这些化合物投入生产和测试，以帮助减轻全球范围内的驱虫感染。**