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Title: Spliced leader trans-splicing : a target for the identification of novel anthelmintic drugs
Author: Pandarakalam, George Cherian
ISNI:       0000 0004 5922 2353
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2016
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Nematodes are ubiquitous organisms on our planet that include both free-living and parasitic species. Parasitic nematodes infect humans, livestock and agricultural crop plants. The burden of disease caused by these nematodes globally is enormous, resulting in a huge economic impact through a decline in human health, animal health and significant crop loss to the agriculture industry. The current major practice to the treatment of nematode infections in humans and veterinary animals is via the administration of a relatively small number of anthelmintic drugs. Repeated usage of the current anthelmintics has resulted in the rapid emergence of nematode strains resistant to one or several different classes of the anthelmintic compounds. This highlights the need for new drugs against novel targets. An ideal drug target is one that is confined to the infecting nematodes and not present in the hosts. One such target is Spliced Leader (SL) trans-splicing, a process that occurs during mRNA maturation in certain groups of eukaryotes like nematodes and involves the addition of a short (20-40 nucleotides) RNA, called the spliced leader RNA, to the 5' end of a subset of pre-mRNAs. SL trans-splicing has been identified in all nematode species studied to date, suggesting that it is a phylum-wide process, but it is absent in vertebrates and plants, the major hosts for parasitic nematodes. This thesis presents the development and optimisation of an in vivo assay in the model nematode Caenorhabditis elegans to screen for novel compounds that specifically inhibit SL trans-splicing in nematodes, and to explore the potential to develop those compounds into patentable drugs. The assay is based on the expression of a fluorescent protein marker (Green Fluorescent Protein) in C. elegans in response to decreased SL trans-splicing. I have optimised the transgenic C. elegans strain used in this assay by incorporation of conditional sterility and permeability mutations. Using this assay, I have also tested and proved the inhibitory effect of the natural antibiotic sinefungin on the SL trans-splicing process in C. elegans. Using this compound, I have explored the potential of developing the in vivo assay in C. elegans into a semi-automated highthroughput screen (HTS) and have started with the screening of available libraries containing bioavailable drugs or small molecules.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Anthelmintics ; Nematodes ; RNA splicing