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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ftdoajarticles:oai:doaj.org/article:abaa115946af4e45b4a03469ea0cec2b 2023-05-15T15:08:39+02:00 Identification of novel modulators of a schistosome transient receptor potential channel targeted by praziquantel. Evgeny G Chulkov Emery Smith Claudia M Rohr Nawal A Yahya Sang-Kyu Park Louis Scampavia Timothy P Spicer Jonathan S Marchant 2021-11-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0009898 https://doaj.org/article/abaa115946af4e45b4a03469ea0cec2b EN eng Public Library of Science (PLoS) https://doi.org/10.1371/journal.pntd.0009898 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0009898 https://doaj.org/article/abaa115946af4e45b4a03469ea0cec2b PLoS Neglected Tropical Diseases, Vol 15, Iss 11, p e0009898 (2021) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2021 ftdoajarticles https://doi.org/10.1371/journal.pntd.0009898 2022-12-30T19:24:48Z 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. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 15 11 e0009898 |
institution |
Open Polar |
collection |
Directory of Open Access Journals: DOAJ Articles |
op_collection_id |
ftdoajarticles |
language |
English |
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. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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 in Journal/Newspaper |
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://doi.org/10.1371/journal.pntd.0009898 https://doaj.org/article/abaa115946af4e45b4a03469ea0cec2b |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 15, Iss 11, p e0009898 (2021) |
op_relation |
https://doi.org/10.1371/journal.pntd.0009898 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0009898 https://doaj.org/article/abaa115946af4e45b4a03469ea0cec2b |
op_doi |
https://doi.org/10.1371/journal.pntd.0009898 |
container_title |
PLOS Neglected Tropical Diseases |
container_volume |
15 |
container_issue |
11 |
container_start_page |
e0009898 |
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1766339966272536576 |