Sunday, October 13, 2024
10/13/2024
PROJECT SUMMARY The parasitic infection schistosomiasis afflicts over 200 million people worldwide and is clinically treated using a single drug, praziquantel (±PZQ). Although ±PZQ has served as a stalwart anthelmintic for decades, the molecular basis of action of this drug remains undefined. This lack of mechanistic knowledge impedes rational design of alternative therapeutics and is worrisome in the face of emergence of schistosome strains exhibiting refractoriness to ±PZQ exposure given ±PZQ is ineffective against all parasitic life cycle stages. Insight into the targets of ±PZQ action, and their effectors, is therefore needed to develop improved anthelmintic therapies. This R01 application is based around preliminary data supporting a premise that PZQ is a serotonin-like ligand in both the parasite and the human host. Our laboratory has recently identified targets for both R-PZQ and S- PZQ, the two enantiomers in the clinical formulation of ±PZQ. R-PZQ is a ligand at the human 5-HT2B G protein coupled receptor (5-HT2B GPCR), and S-PZQ is a serotonergic regulator of the human transient receptor potential melastatin 8 ion channel (TRPM8). These findings are significant as they (i) provide clues to the likely targets of PZQ enantiomers in the parasite (5-HT GPCRs & TRP channels) and (ii) demonstrate that PZQ does not act as a selective antiparasitic, but also is active in the host. Notably ±PZQ acutely changes blood vessel tone within the mesenteric blood vessels where the adult worms reside. Chronic engagement of 5-HT GPCRs in hepatic stellate cells inhibited fibrotic changes caused by inflammatory reactions to worm eggs deposited in host tissues. Coalescing such beneficial host and deleterious parasitic activities provides a novel route to generating improved antiparasitic therapies that kill worms and prevent the tissue damage they cause. Based on our discoveries, we will map the binding sites of R-PZQ on 5-HT2BR, and S-PZQ on TRPM8 and use these binding poses to identify similar binding architectures in schistosome bioaminergic GPCRs (Aim 1) and TRP channels (Aim 2). Following this strategy, we have recently identified a schistosome TRP channel that is regulated by PZQ (10) – the first target of PZQ ever identified in a flatworm. Finally, we will address the clinical significance of host bioactivity of anthelmintics (Aim 3) in terms of acute effects on the vasculature, and chronic effects on hepatic stellate cells that initiate fibrogenic changes underpinning many of the pathologies of chronic schistosomiasis. Our collaborative team bring together expertise in 5-HT2B receptor structure, TRP channel biology and blood vessel physiology to execute activities from molecular (receptor structure) to in vivo pathology (mechanisms regulating parasite infection and liver disease). If successful, our activities will resolve targets and effectors for ±PZQ that will enable development of better anthelmintic therapies and adjuncts.
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