Discovery of novel antiparasitics that target a pharmacologically atypical schistosome Transient Receptor Potential (TRP) ion channel

University Of Pennsylvania, Philadelphia PA

Investigators

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Abstract

Project Summary: Parasitic flatworms of the genus Schistosoma cause schistosomiasis, a neglected tropical disease affecting hundreds of millions of people worldwide. There is no vaccine, and only a single drug, praziquantel (PZQ), is available for treatment and control. Though indispensable, PZQ has significant shortcomings, and reliance on only one drug for such a highly prevalent disease is dangerous, particularly in light of reports of PZQ-resistant worms. The need for new therapeutics is therefore urgent. Ion channels underlie electrical excitability in cells, and are validated targets for drugs and toxins, including a large number of current anthelmintics. However, only a few parasite ion channel families have been exploited as drug targets. In this project, we focus on one member (SmTRPA) of a largely unexplored family of schistosome ion channels, the transient receptor potential (TRP) channels. TRP channels comprise a diverse family of ion channels that share a common core structure, but are widely varied in their activation mechanisms and ion selectivity. TRP channels are critical to transducing a wide range of sensory signals. They are also involved in a variety of other functions, such as regulation of intracellular and organellar ion homeostasis, and are currently under intense investigation as therapeutic targets for several conditions. We hypothesize that TRP channels from schistosomes and perhaps other parasitic platyhelminths may be excellent targets for new anthelmintics, as they are likely essential for fulfillment of the parasite life cycle, which depends on external cues for host-finding and migration to predilection sites, as well as regulation of neuromuscular activity and ion homeostasis. Our published and preliminary studies show that SmTRPA, the single S. mansoni TRPA1-like channel, can be targeted to impair normal neuromuscular function. Notably, SmTRPA also exhibits at least some of the pharmacology of another type of TRP channel, TRPV1. This mixed TRPV1/TRPA1 pharmacology is particularly intriguing, as TRPV channels are not represented in schistosome (or other parasitic platyhelminth) genomes. Preliminary functional expression studies using Ca2+ imaging are consistent with this interpretation. In this exploratory project, we will use calcium imaging in a high-throughput screen to identify small molecules that selectively activate this pharmacologically atypical TRP channel (Aim 1). This aim will provide lead scaffolds for further characterization and refinement. In Aim 2, we will test responses of schistosomes at different life-cycle stages to known and newly-identified SmTRPA modulators, measuring parameters such as worm survival, motility, male-female pairing, and egg production. This aim will provide a deeper understanding of the effects of known SmTRPA modulators, and assess newly-identified SmTRPA modulators for antischistosomal activity. This project could eventually lead to development of new antischistosomals that target a novel receptor, and could serve as a model for discovery of other anthelmintics that target TRP channels from other parasitic pathogens.