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:79a1cd713faf4c3d89313b9826e1c45d 2023-05-15T15:15:30+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://doaj.org/article/79a1cd713faf4c3d89313b9826e1c45d EN eng Public Library of Science (PLoS) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8565742/?tool=EBI https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 https://doaj.org/article/79a1cd713faf4c3d89313b9826e1c45d PLoS Neglected Tropical Diseases, Vol 15, Iss 11 (2021) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2021 ftdoajarticles 2022-12-31T09:08:36Z 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 ... Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic |
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Open Polar |
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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. 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 ... |
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://doaj.org/article/79a1cd713faf4c3d89313b9826e1c45d |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 15, Iss 11 (2021) |
op_relation |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8565742/?tool=EBI https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 https://doaj.org/article/79a1cd713faf4c3d89313b9826e1c45d |
_version_ |
1766345867133976576 |