Towards validation of the sigma class GSTs from the liver fluke Fasciola hepatica as chemotherapeutic targets

Crynodeb

The liver fluke Fasciola hepatica along with its relative Fasciola gigantica are neglected parasites of increasing importance. These parasites cause over $3 billion of losses to the agricultural industry, along with around 180 million humans predicted to be at risk of infection globally. Due to lack of adequate protection observed in the current development of vaccines for Fasciola and the increasing evidence of resistance to the mainstay anthelmintic Triclabendazole (TCBZ), it is important to develop new anthelmintic compounds effective against these parasites. Previously, anthelmintic compound development for F. hepatica has largely been based on randomised compound screening. However, the current work has taken an alternative approach, investigating compounds targeted on a known key protein target group, the Sigma class GSTs. Sigma GSTs in trematodes have previously demonstrated involvement in both detoxification and interaction with the host immune environment. Therefore, inhibition of Sigma GSTs would likely be detrimental to the parasite. Increased genomic and transcriptomic data has allowed confirmation and elucidation of a new Sigma GST present in both F. hepatica and F. gigantica. Furthermore, phylogenetic analysis has uncovered a potential pattern of interest involving the Sigma GSTs within extracellular vesicles (EVs) with a parasite or immune evasion selectivity role. The successful expression of multiple Fasciola Sigma class GSTs, along with the chemical synthesis of glutathioneconjugate inhibitor compounds, has allowed for the determination of a lead compound, designated as Ha14, within this study. Ha14 demonstrated inhibitory effectivity on both Sigma and Mu class GSTs of F. hepatica as well as rFgGST-S1 from F. gigantica at ≤ 5 µM levels and, despite lacking selectivity compared to a human orthologue, was observed to be tolerated at higher concentrations following toxicity analysis. Consequently, Ha14 was trialled in vitro for anthelmintic effects on adults and potential fecundity effects and demonstrated equivalent or improved activities in comparison to TCBZ and its active sulphoxide metabolite. Results suggest that inhibition of Sigma and Mu class GSTs within F. hepatica offers alternative compound targeting routes to TCBZ. In addition, the detoxification roles of GSTs suggest a high potential for synergistic application of glutathione-conjugates in combination with TCBZ, facilitating a dual role anthelmintic compound with increased efficacy.

Dyddiad Dyfarnu	2019
Iaith wreiddiol	Saesneg
Sefydliad Dyfarnu	Prifysgol Aberystwyth
Goruchwyliwr	Peter Brophy (Goruchwylydd) & Russ Morphew (Goruchwylydd)