G-quadruplexes in the parasitic platyhelminth Schistosoma mansoni: identification and anthelmintic drugability

Tue10  Apr05:15pm(15 mins)
Where:
Stream 3 - Physics 0.15 Main

Authors

H Craven1; H Whiteland1; M Swain1; L Hurley2; K F Hoffmann1
1 Aberystwyth University, UK;  2 University of Arizona, United States

Discussion

Guanine rich sequences of DNA can fold into alternative structures called G-Quadruplexes (GQs) and form in vivo in single cell as well as multicellular organisms. Schistosoma mansoni is a multicellular parasitic platyhelminth and a causative agent of schistosomiasis, which affects some 200 million people annually. New S. mansoni drugs and therapeutic targets are urgently needed as potential for resistance to the current chemotherapy, praziquantel, increases. As GQs have been targeted in drug development pipelines ranging from cancer to human African trypanosomiasis (HAT or sleeping sickness), they could provide a new target for progressing novel anti-schistosomal agents. < p> < p> Here, computational methodologies to identify putative quadruplex structures (PQS) within the S. mansoni genome were performed. The genome was searched for sequences that satisfy the algorithm (G≥3N1-7 G≥3N1-7 G≥3N1-7 G≥3N1-7)n using Quadparser software. A total 1,145 PQS were established (409 in intragenic regions, 370 in intergenic regions). Cross referencing sequences with the annotated genome illustrated that of the 409 PQS found in intragenic regions, 354 occurred within introns and only 40 were found within exons. When stringency was relaxed to N1-20, total PQS increased to 7,913 (2,576 within intragenic regions, 2,874 within intergenic regions), with 2,149 mapped to introns and 293 found in exons. A list of putative quadruplex sequences most likely to fold in vivo are currently being assessed. < p> Roboworm, our in-house, high-throughput screening platform was utilised to assess anthelmintic efficacy of Quarfloxin, a compound known to bind GQs and affect rRNA biogenesis, on Schistosoma larva (schistosomula). After 72 hours, significant reduction in viability measures were detected in schistosomula dosed with quarfloxin (IC50motility ≤ 1.42 µM; IC50phenotype ≤ 1.45 µM). Quarfloxin efficacy was further assessed on adult worm (and 3 week juvenile) parasites, and was found to impair adult parasite motility up to 5 µM, with a greater observed effect on males than females. However, oviposition in females was disrupted up to 0.625 µM. < p> This work represents the first evidence of PQS within the S. mansoni genome and the first to test GQ targeting molecules on the parasite. While the mechanism of quarfloxin action against S. mansoni must be confirmed (inhibition of PolI and/or PolII transcription), this exciting preliminary data suggests that GQs could be targeted in developing alternative routes of treatment for a neglected tropical disease.
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