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Assay Development as Critical for Drug Discovery Against Human Intestinal Parasites /


The soil-transmitted helminthes infect up to two billion people and are leading causes of morbidity in the developing world. The only subclass of drugs effective against these parasites in mass drug administration is facing the threat of resistance and is not efficacious against all parasites. With infection rates and demographics this overwhelming, there is a growing need towards the discovery of new and more efficacious anthelmintics. Past anthelmintic discovery efforts have traditionally utilized veterinary (non-human) parasitic nematodes or non-parasitic nematodes altogether. We ask in the present study - are there superior alternatives to current anthelmintic discovery systems, specifically against human intestinal parasites? In answering this question, I develop and test a moderate-throughput 96-well format assay for anthelmintic screening against the free- living nematode Caenorhabditis elegans, and embryonic/ larval stages of the parasitic nematodes Heligmosomoides bakeri, and Ancylostoma ceylanicum. This assay differs from existing larval assays in its capacity to look at a wider range of the parasite's life cycle and, in the case of A. ceylanicum, to incorporate a zoonotic human parasitic nematode. The assay was utilized in screening two small compound libraries to gauge the general overlap of hits between various nematodes and assess the feasibility of these methods. Significantly, compounds that hit on a human parasite would not necessarily be detected on a murine parasite or free-living nematode of the same clade. I discuss the implications of these results on future drug screening, which suggests that a human parasitic nematode could be successfully used for anthelmintic discovery

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