Open AccessIdentification of novel modulators of a schistosome transient receptor potential channel targeted by praziquantel
Author(s) -
Evgeny G. Chulkov,
Emery Smith,
Claudia Rohr,
Nawal A Yahya,
Sang-Kyu Park,
Louis Scampavia,
Timothy Spicer,
Jonathan S. Marchant
Publication year - 2021
Publication title -
plos neglected tropical diseases
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.99
H-Index - 135
eISSN - 1935-2735
pISSN - 1935-2727
DOI - 10.1371/journal.pntd.0009898
Subject(s) - druggability , praziquantel , drug discovery , biology , schistosoma mansoni , computational biology , schistosoma , pharmacology , neglected tropical diseases , virtual screening , phenotypic screening , anthelmintic , flatworm , schistosomiasis , bioinformatics , medicine , phenotype , immunology , genetics , disease , helminths , gene , ecology
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 (TRPM PZQ ) to mediate sustained Ca 2+ influx and worm paralysis. As a druggable target present in many parasitic flatworms, TRPM PZQ 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 Ca 2+ -based reporter assay for Schistosoma mansoni TRPM PZQ ( Sm .TRPM PZQ ) activity enabling a high throughput screening (HTS) approach. This methodology will enable further HTS efforts against Sm .TRPM PZQ as well as other flatworm ion channels. A pilot screen of ~16,000 compounds yielded a novel activator of Sm .TRPM PZQ , and numerous potential blockers. The new activator of Sm .TRPM PZQ 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 .TRPM PZQ agonist underscores the validity of TRPM PZQ as a druggable target for antischistosomal ligands.