Medical College of Wisconsin
CTSICores SearchResearch InformaticsREDCap

Ergot Alkaloids (Re)generate New Leads as Antiparasitics. PLoS Negl Trop Dis 2015;9(9):e0004063

Date

09/15/2015

Pubmed ID

26367744

Pubmed Central ID

PMC4569474

DOI

10.1371/journal.pntd.0004063

Scopus ID

2-s2.0-84943179139   15 Citations

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.

Author List

Chan JD, Agbedanu PN, Grab T, Zamanian M, Dosa PI, Day TA, Marchant JS

Author

Jonathan S. Marchant PhD Chair, Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Antiparasitic Agents
Drug Discovery
Ergot Alkaloids
Platyhelminths
Praziquantel
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a