Analysis of quadruplex DNA structures in schistosome parasites and their potential as therapeutic targets for the neglected infectious disease schistosomiasis.

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Supervisors: Karl F Hoffmann ([Email Address Removed]); Helen Whiteland ([Email Address Removed]) and Laurence Hurley (University of Arizona; [Email Address Removed])

Schistosomiasis is a neglected infectious disease that annually kills 200,000 people living in the poorest communities found throughout Africa, South East Asia and South America (although now also found in Europe). Praziquantel is the current drug used to treat the disease, but with wide spread use, the risk of developing drug resistant parasites is high. Therefore, the drive to identify new chemotherapies (preferably with a known mechanism of action) and targets is of paramount importance.
One target of interest is quadruplex DNA, which form in regions that are rich in guanine/cytosine. Four stranded DNA structures are formed when the Hoogsteen hydrogen-bonded guanine (G) tetrad is stacked one on top of another. On either end of the stacked G-tetrads are loops that form from intervening nucleotides that are not usually located within the tetrad itself. Pioneering studies, conducted at the University of Arizona (Laurence Hurley Lab), have clearly demonstrated the importance of these structures in regulating gene expression of key transcription factors. There have been no corresponding studies, to date, attempting to identify quadruplex structures in Schistosoma mansoni (the parasite species studied within the Hoffmann lab) or to understand their relevance in parasite gene expression regulation. Due to their importance in maintaining transcriptional control in other eukaryotes, we contend that these structures play important roles during the life cycle of the parasite and are, thus, suitable targets for anti-schistosomal drug discovery. We are now looking to appoint a talented and ambitious PhD student to join our interdisciplinary drug discovery team and pursue a research project encompassing the following three aims:

1. Identify putative quadruplex DNA structures within the Schistosoma mansoni genome using QGRS-Mapper and linking this information to chromosomal position and lifecycle transcriptional profiles (IBERS).
2. Verify putative quadruplex structures by combinatorial NMR, CD, UV spectroscopy and thermal denaturation methodologies (U of Arizona).
3. Test quadruplex-binding drugs against schistosomes (with our American colleagues; U of Arizona) to see whether this affects global (RNA-seq)- or targeted (qRT-PCR)- schistosome transcription as well as parasite phenotype and motility as screened on the Roboworm drug-discovery platform (IBERS).

This PhD studentship provides an opportunity to gain world-class expertise in genomics, transcriptomics, structural biology, drug screening and bioinformatics, particularly as they are relevant to solving the global challenge of identifying novel anthelmintics. Training will be given in modern genome/transcriptome/structural biology analyses as well as in whole organism drug screening methodologies. The selected candidate will join a highly successful schistosomiasis research team (http://www.aber.ac.uk/en/ibers/research/research-groups/parasitology_epidemiology_group/hoffmann_research_lab/) focused on drug discovery. They will also benefit from a placement with the School of Pharmacy, University of Arizona (http://www.pharmacy.arizona.edu/directory/laurence-hurley-phd), where they will gain experience relevant to future employability in applied aspects of structural biology and medicinal chemistry.