Inhibitors of gene expression to treat parasitic nematode infections

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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).