Discussion

>300 million people are infected with parasitic flatworms each year.  Flatworm diseases sit among 20 neglected tropical diseases (NTDs) recognised by the United Nations World Health Organization (WHO), with recent estimates attributing losses of >6.2 million disability-adjusted life years (DALYs) annually to such infections.  Limited flatworm vaccines and increasing anthelmintic resistance threaten the sustainability of control and underscore the need for novel flatworm anthelmintic development.  Ion channels are involved in a vast array of cellular functions, underpinning behaviours key to survival including neuromuscular function. Despite the rich pharmacology of ion channels and their current use in the treatment of nematode infections, praziquantel is the only drug linked to ion channel dysregulation in parasitic flatworms. A primary limitation to further exploiting ion channel networks in flatworm drug development is a lack of knowledge on their fundamental biology within these organisms.  This work showcases the use of recent genomic datasets to identify and evaluate ligand-gated ion channels (LGICs) as potential anthelmintic drug targets for parasitic flatworms.  Using a Hidden Markov Model (HMM) based approach, predicted protein datasets were mined for LGIC sequences.  Initial work focussed on characterising ion channels in liver fluke, Fasciola hepatica, describing 53 high confidence LGICs.  The dataset includes obvious potential drug targets such as members of the Cys-loop superfamily (nicotinic acetylcholine and glutamate-gated chloride channels) and ionotropic glutamate receptors.  Less obvious drug targets such as amiloride-sensitive sodium channels, ATP-gated channels and inositol 1,4,5-trisphosphate binding receptors were also identified.  In silico analysis was expanded to include datasets for 30 other flatworm species (free living and parasitic) allowing for a deeper characterisation of ion channel structure and function.  Combining in silico analysis with our functional genomic platform offers a much-improved ability to characterise ion channel function and evaluate flukicide-target and spectrum potential.