Abstract
Schistosomiasis is a debilitating tropical disease caused by infection with parasitic blood flukes. Approximately 260 million people are infected worldwide, underscoring the clinical and socioeconomic impact of this chronic infection. Schistosomiasis is treated with the drug praziquantel (PZQ), which has proved the therapeutic mainstay for over three decades of clinical use. However, the molecular target(s) of PZQ remain undefined. Here we identify a molecular target for the antischistosomal eutomer — (R)-PZQ — which functions as a partial agonist of the human serotoninergic 5HT2B receptor. (R)-PZQ modulation of serotoninergic signaling occurs over a concentration range sufficient to regulate vascular tone of the mesenteric blood vessels where the adult parasites reside within their host. These data establish (R)-PZQ as a G-protein-coupled receptor ligand and suggest that the efficacy of this clinically important anthelmintic is supported by a broad, cross species polypharmacology with PZQ modulating signaling events in both host and parasite.
Highlights
Schistosomiasis is a debilitating tropical disease caused by infection with parasitic blood flukes
These data will prioritize future screening of flatworm G-protein-coupled receptor (GPCR) for a (R)-PZQ target and underscore an activity of (R)-PZQ on 5-HT2B receptor (5-HT2BR) signaling in the human host, manifest within the vascular beds where the adult parasites reside
On the basis of these observations, we considered whether PZQ acts as a direct serotoninergic ligand to oppose 5-HT evoked G-protein-coupled receptor (GPCR) signaling
Summary
Schistosomiasis is a debilitating tropical disease caused by infection with parasitic blood flukes. These data will prioritize future screening of flatworm GPCRs for a (R)-PZQ target and underscore an activity of (R)-PZQ on 5-HT2BR signaling in the human host, manifest within the vascular beds where the adult parasites reside. The top candidate from the docking to pocket classification (‘dpc’ models) was the human 5-HT2B receptor (5-HT2BR), with (R)-PZQ possessing the highest predicted affinity (Supplementary Table 1).
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