Identification of novel modulators of a schistosome transient receptor potential channel targeted by praziquantel.

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), emp...

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Autores principales: Evgeny G Chulkov, Emery Smith, Claudia M Rohr, Nawal A Yahya, Sang-Kyu Park, Louis Scampavia, Timothy P Spicer, Jonathan S Marchant
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Publicado: Public Library of Science (PLoS) 2021
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spelling oai:doaj.org-article:abaa115946af4e45b4a03469ea0cec2b2021-12-02T20:23:23ZIdentification of novel modulators of a schistosome transient receptor potential channel targeted by praziquantel.1935-27271935-273510.1371/journal.pntd.0009898https://doaj.org/article/abaa115946af4e45b4a03469ea0cec2b2021-11-01T00:00:00Zhttps://doi.org/10.1371/journal.pntd.0009898https://doaj.org/toc/1935-2727https://doaj.org/toc/1935-2735Given 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.Evgeny G ChulkovEmery SmithClaudia M RohrNawal A YahyaSang-Kyu ParkLouis ScampaviaTimothy P SpicerJonathan S MarchantPublic Library of Science (PLoS)articleArctic medicine. Tropical medicineRC955-962Public aspects of medicineRA1-1270ENPLoS Neglected Tropical Diseases, Vol 15, Iss 11, p e0009898 (2021)
institution DOAJ
collection DOAJ
language EN
topic Arctic medicine. Tropical medicine
RC955-962
Public aspects of medicine
RA1-1270
spellingShingle Arctic medicine. Tropical medicine
RC955-962
Public aspects of medicine
RA1-1270
Evgeny G Chulkov
Emery Smith
Claudia M Rohr
Nawal A Yahya
Sang-Kyu Park
Louis Scampavia
Timothy P Spicer
Jonathan S Marchant
Identification of novel modulators of a schistosome transient receptor potential channel targeted by praziquantel.
description 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.
format article
author Evgeny G Chulkov
Emery Smith
Claudia M Rohr
Nawal A Yahya
Sang-Kyu Park
Louis Scampavia
Timothy P Spicer
Jonathan S Marchant
author_facet Evgeny G Chulkov
Emery Smith
Claudia M Rohr
Nawal A Yahya
Sang-Kyu Park
Louis Scampavia
Timothy P Spicer
Jonathan S Marchant
author_sort Evgeny G Chulkov
title Identification of novel modulators of a schistosome transient receptor potential channel targeted by praziquantel.
title_short Identification of novel modulators of a schistosome transient receptor potential channel targeted by praziquantel.
title_full Identification of novel modulators of a schistosome transient receptor potential channel targeted by praziquantel.
title_fullStr Identification of novel modulators of a schistosome transient receptor potential channel targeted by praziquantel.
title_full_unstemmed Identification of novel modulators of a schistosome transient receptor potential channel targeted by praziquantel.
title_sort identification of novel modulators of a schistosome transient receptor potential channel targeted by praziquantel.
publisher Public Library of Science (PLoS)
publishDate 2021
url https://doaj.org/article/abaa115946af4e45b4a03469ea0cec2b
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