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
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270
Acceso en línea:	https://doaj.org/article/79a1cd713faf4c3d89313b9826e1c45d
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spelling	oai:doaj.org-article:79a1cd713faf4c3d89313b9826e1c45d2021-11-11T09:25:05ZIdentification of novel modulators of a schistosome transient receptor potential channel targeted by praziquantel1935-27271935-2735https://doaj.org/article/79a1cd713faf4c3d89313b9826e1c45d2021-11-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8565742/?tool=EBIhttps://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. Author summary The drug praziquantel is used to treat diseases caused by parasitic flatworms. Praziquantel is an old drug, and there is a need to identify novel treatments that retain desirable features and improve weaknesses in the mode of PZQ action. One way to do this is to identify new drugs that exploit vulnerabilities in the same drug target but work in slightly differently ways. Here, we have optimized high throughput screening methods to pharmacologically profile a parasitic flatworm ion channel targeted by PZQ. We have identified several new chemical structures that interact with this channel complex. These ligands provide new opportunity for developing tools to manipulate flatworm biology and potentially new trajectories for anthelmintic drug development.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 (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. Author summary The drug praziquantel is used to treat diseases caused by parasitic flatworms. Praziquantel is an old drug, and there is a need to identify novel treatments that retain desirable features and improve weaknesses in the mode of PZQ action. One way to do this is to identify new drugs that exploit vulnerabilities in the same drug target but work in slightly differently ways. Here, we have optimized high throughput screening methods to pharmacologically profile a parasitic flatworm ion channel targeted by PZQ. We have identified several new chemical structures that interact with this channel complex. These ligands provide new opportunity for developing tools to manipulate flatworm biology and potentially new trajectories for anthelmintic drug development.
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/79a1cd713faf4c3d89313b9826e1c45d
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Identification of novel modulators of a schistosome transient receptor potential channel targeted by praziquantel

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