A Miniaturized Screen of a Schistosoma mansoni Serotonergic G Protein-Coupled Receptor Identifies Novel Classes of Parasite-Selective Inhibitors

J.D. Chan, J.D. McCorvy, S. Acharya, M.E. Johns, T.A. Day, B.L. Roth, J.S. Marchant

Research output: Contribution to journalArticlepeer-review

30 Citations (Scopus)
245 Downloads (Pure)

Abstract

Schistosomiasis is a tropical parasitic disease afflicting ~200 million people worldwide and current therapy depends on a single drug (praziquantel) which exhibits several non-optimal features. These shortcomings underpin the need for next generation anthelmintics, but the process of validating physiologically relevant targets (‘target selection’) and pharmacologically profiling them is challenging. Remarkably, even though over a quarter of current human therapeutics target rhodopsin-like G protein coupled receptors (GPCRs), no library screen of a flatworm GPCR has yet been reported. Here, we have pharmacologically profiled a schistosome serotonergic GPCR (Sm.5HTR) implicated as a downstream modulator of PZQ efficacy, in a miniaturized screening assay compatible with high content screening. This approach employs a split luciferase based biosensor sensitive to cellular cAMP levels that resolves the proximal kinetics of GPCR modulation in intact cells. Data evidence a divergent pharmacological signature between the parasitic serotonergic receptor and the closest human GPCR homolog (Hs.5HTR7), supporting the feasibility of optimizing parasitic selective pharmacophores. New ligands, and chemical series, with potency and selectivity for Sm.5HTR over Hs.5HTR7 are identified in vitro and validated for in vivo efficacy against schistosomules and adult worms. Sm.5HTR also displayed a property resembling irreversible inactivation, a phenomenon discovered at Hs.5HTR7, which enhances the appeal of this abundantly expressed parasite GPCR as a target for anthelmintic ligand design. Overall, these data underscore the feasibility of profiling flatworm GPCRs in a high throughput screening format competent to resolve different classes of GPCR modulators. Further, these data underscore the promise of Sm.5HTR as a chemotherapeutically vulnerable node for development of next generation anthelmintics. © 2016 Chan et al.
Original languageEnglish
Pages (from-to)1-26
JournalPLoS Pathogens
Volume12
Issue number5
DOIs
Publication statusPublished - 17 May 2016
Externally publishedYes

Bibliographical note

cited By 10

Keywords

  • bromocriptine
  • dihydroergotamine
  • ergotamine
  • G protein coupled receptor
  • lisuride
  • metitepine
  • praziquantel
  • rhodopsin
  • serotonin receptor
  • transcriptome
  • G protein coupled receptor, animal experiment
  • animal model
  • Article
  • Biomphalaria glabrata
  • biosensor
  • cAMP assay
  • cell viability
  • controlled study
  • DNA sequence
  • drug exposure
  • female
  • high throughput screening
  • human
  • human cell
  • male
  • molecular cloning
  • nonhuman
  • polymerase chain reaction
  • Schistosoma mansoni
  • schistosomiasis
  • schistosomiasis mansoni
  • schistosomulum
  • structure activity relation
  • Western blotting
  • animal
  • HEK293 cell line
  • metabolism
  • mouse
  • preclinical study
  • procedures
  • schistosomiasis mansoni, Animals
  • Blotting, Western
  • Drug Evaluation, Preclinical
  • Female
  • HEK293 Cells
  • High-Throughput Screening Assays
  • Humans
  • Mice
  • Receptors, G-Protein-Coupled
  • Schistosomiasis mansoni

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