Inhibitors of gene expression to treat parasitic nematode infections

寄生线虫感染对全球人类健康、福祉和经济产生影响;它们对人类宿主的健康产生直接影响，并通过感染牲畜和农作物，危及粮食安全并损害经济可持续性。治疗动物和人类寄生线虫的药物有限，对现有疗法的耐药性是一个日益增长的挑战。植物寄生线虫的控制通常依赖于苛刻的、破坏环境的土壤处理。因此，迫切需要开发新的、广泛特异性的药物治疗。线虫使用一种不寻常的基因表达策略，剪接前导反式剪接，这是缺乏其脊椎动物和植物宿主，使其成为药物开发目标的理想来源。剪接前导序列反式剪接依赖于一组必需的、高度保守的线虫特异性蛋白质和非编码RNA，Aberdeen蠕虫实验室（https：//www.aberdeenwormlab.org/）的研究旨在利用模型线虫C的许多实验优势，了解指导线虫剪接前导序列反式剪接的分子机制。优雅该项目的重点是利用我们最近的工作，开发高通量检测，可用于识别或工程设计新的化合物作为剪接前导反式剪接机制的抑制剂。因此，这些化合物可以被开发成损害寄生线虫的生存能力和繁殖能力的药物。该研究将与BioAscent Discovery Ltd.（纽豪斯，苏格兰）合作进行，该公司在药物发现方面拥有丰富的经验，从体外试验开发到临床治疗候选药物的鉴定和开发。该项目将适合希望在学术和商业环境中获得药物发现和开发策略经验的学生。它涉及将从基础生物化学和分子遗传学中获得的知识应用于新型小分子抑制剂的发现和开发，以及探索使用最近开发的新策略，如RIBOTAC（核糖核酸酶靶向嵌合体）和PROTAC（蛋白水解靶向嵌合体）来抑制剪接前导序列反式剪接（参见https://doi.org/10.1016/j.chembiol.2019.07.015了解这两种方法的简要介绍）。

Parasitic nematode infections have global human health, welfare, and economic impacts; they have direct effects on the health of their human hosts and through infections of livestock and crop plants, they jeopardise food security and compromise economic sustainability. There is a limited pool of drugs to treat animal and human parasitic nematodes and resistance to existing therapeutics is a growing challenge. Control of plant parasitic nematodes is frequently reliant upon harsh, environmentally damaging soil treatments. There is thus a pressing need to develop new, broad-specificity drug treatments. Nematodes use an unusual gene expression strategy, spliced leader trans-splicing, which is absent from their vertebrate and plant hosts, making it an ideal source of drug development targets. Spliced leader trans-splicing is dependent on a set of essential, highly conserved, nematode-specific proteins and non-coding RNAs and research in the Aberdeen Worm Lab (https://www.aberdeenwormlab.org/) is directed towards understanding the molecular machinery that directs nematode spliced leader trans-splicing, using the many experimental advantages of the model nematode C. elegans. This project is focused on exploiting our recent work to develop high-throughput assays that can be used to identify or engineer novel compounds as inhibitors of the spliced leader trans-splicing machinery. Such compounds can thus be developed into drugs that impair the viability and reproductive capacity of parasitic nematodes. The research will be conducted in collaboration with BioAscent Discovery Ltd. (Newhouse, Scotland), who have extensive experience of drug discovery, ranging from in vitro assay development through to identification and development of clinical therapeutic candidates. The project would suit a student who wants to gain experience of drug discovery and development strategies, in both an academic and commercial setting. It involves applying the knowledge gained from basic biochemistry and molecular genetics to the discovery and development of novel, small-molecule inhibitors, as well as exploring the use of recently developed novel strategies such as RIBOTACs (Ribonuclease Targeting Chimeras) and PROTACs (Proteolysis Targeting Chimeras) to inhibit spliced leader trans-splicing (see https://doi.org/10.1016/j.chembiol.2019.07.015 for a brief introduction of these two approaches).