Abstract
Praziquantel (PZQ) is a key therapy for treatment of parasitic flatworm infections of humans and livestock, but the mechanism of action of this drug is unresolved. Resolving PZQ-engaged targets and effectors is important for identifying new druggable pathways that may yield novel antiparasitic agents. Here we use functional, genetic and pharmacological approaches to reveal that serotonergic signals antagonize PZQ action in vivo. Exogenous 5-hydroxytryptamine (5-HT) rescued PZQ-evoked polarity and mobility defects in free-living planarian flatworms. In contrast, knockdown of a prevalently expressed planarian 5-HT receptor potentiated or phenocopied PZQ action in different functional assays. Subsequent screening of serotonergic ligands revealed that several ergot alkaloids possessed broad efficacy at modulating regenerative outcomes and the mobility of both free living and parasitic flatworms. Ergot alkaloids that phenocopied PZQ in regenerative assays to cause bipolar regeneration exhibited structural modifications consistent with serotonergic blockade. These data suggest that serotonergic activation blocks PZQ action in vivo, while serotonergic antagonists phenocopy PZQ action. Importantly these studies identify the ergot alkaloid scaffold as a promising structural framework for designing potent agents targeting parasitic bioaminergic G protein coupled receptors.
Highlights
Schistosomiasis is a neglected tropical disease that infects over 200 million people worldwide, burdening economies with an annual loss of several million disability-adjusted life years [1,2,3]
We exploit the predictive phenology between free-living planarian regenerative screens and parasitic neuromuscular physiology to reveal a broad efficacy of ergot alkaloids in phenocopying the action of PZQ
The disease is caused by parasitic flatworms of the genus Schistosoma and treatment is largely reliant on a single drug—praziquantel (PZQ), used clinically for over 30 years [4,5,6]
Summary
Schistosomiasis is a neglected tropical disease that infects over 200 million people worldwide, burdening economies with an annual loss of several million disability-adjusted life years [1,2,3]. The disease is caused by parasitic flatworms of the genus Schistosoma and treatment is largely reliant on a single drug—praziquantel (PZQ), used clinically for over 30 years [4,5,6]. Development of alternative therapies to PZQ has been hampered by the fact that the mechanism of action of PZQ remains unresolved and rationally designed derivatives of PZQ typically prove less efficacious [7,14,15]. These longstanding roadblocks impair the iteration of generation antischistosomals needed to counter the likely emergence of PZQ-resistant isolates [16]. Resolution of the pathways engaged by PZQ in vivo is a key priority
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