Faculty Collaboration Database

Identification of novel modulators of a schistosome transient receptor potential channel targeted by praziquantel. PLoS Negl Trop Dis 2021 Nov;15(11):e0009898

Date

11/04/2021

Pubmed ID

34731172

Pubmed Central ID

PMC8565742

DOI

10.1371/journal.pntd.0009898

Scopus ID

2-s2.0-85120649827 (requires institutional sign-in at Scopus site)   10 Citations

Abstract

Given the worldwide burden of neglected tropical diseases, there is ongoing need to develop novel anthelmintic agents to strengthen the pipeline of drugs to combat these burdensome infections. Many diseases caused by parasitic flatworms are treated using the anthelmintic drug praziquantel (PZQ), employed for decades as the key clinical agent to treat schistosomiasis. PZQ activates a flatworm transient receptor potential (TRP) channel within the melastatin family (TRPMPZQ) to mediate sustained Ca2+ influx and worm paralysis. As a druggable target present in many parasitic flatworms, TRPMPZQ is a promising target for a target-based screening campaign with the goal of discovering novel regulators of this channel complex. Here, we have optimized methods to miniaturize a Ca2+-based reporter assay for Schistosoma mansoni TRPMPZQ (Sm.TRPMPZQ) activity enabling a high throughput screening (HTS) approach. This methodology will enable further HTS efforts against Sm.TRPMPZQ as well as other flatworm ion channels. A pilot screen of ~16,000 compounds yielded a novel activator of Sm.TRPMPZQ, and numerous potential blockers. The new activator of Sm.TRPMPZQ represented a distinct chemotype to PZQ, but is a known chemical entity previously identified by phenotypic screening. The fact that a compound prioritized from a phenotypic screening campaign is revealed to act, like PZQ, as an Sm.TRPMPZQ agonist underscores the validity of TRPMPZQ as a druggable target for antischistosomal ligands.

Author List

Chulkov EG, Smith E, Rohr CM, Yahya NA, Park SK, Scampavia L, Spicer TP, Marchant JS

Authors

Evgenii Chulkov Postdoctoral Fellow in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
Jonathan S. Marchant PhD Chair, Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
Sang Kyu Park PhD Research Scientist I 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
Anthelmintics
Calcium
Drug Evaluation, Preclinical
Female
Helminth Proteins
Humans
Male
Mice
Praziquantel
Schistosoma mansoni
Schistosomiasis mansoni
Transient Receptor Potential Channels