Ergot Alkaloids (Re)generate New Leads as Antiparasitics.
Praziquantel (PZQ) is a key therapy for treatment of parasitic flatworm infections of humans and livestock, but the mechanism of action of this drug is unresolved. Resolving PZQ-engaged targets and effectors is important for identifying new druggable pathways that may yield novel antiparasitic agent...
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ftdoajarticles:oai:doaj.org/article:1f81f024f3a24ffda1ff9ec6c880b22b 2023-05-15T15:06:09+02:00 Ergot Alkaloids (Re)generate New Leads as Antiparasitics. John D Chan Prince N Agbedanu Thomas Grab Mostafa Zamanian Peter I Dosa Timothy A Day Jonathan S Marchant 2015-01-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0004063 https://doaj.org/article/1f81f024f3a24ffda1ff9ec6c880b22b EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC4569474?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0004063 https://doaj.org/article/1f81f024f3a24ffda1ff9ec6c880b22b PLoS Neglected Tropical Diseases, Vol 9, Iss 9, p e0004063 (2015) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2015 ftdoajarticles https://doi.org/10.1371/journal.pntd.0004063 2022-12-31T03:35:52Z Praziquantel (PZQ) is a key therapy for treatment of parasitic flatworm infections of humans and livestock, but the mechanism of action of this drug is unresolved. Resolving PZQ-engaged targets and effectors is important for identifying new druggable pathways that may yield novel antiparasitic agents. Here we use functional, genetic and pharmacological approaches to reveal that serotonergic signals antagonize PZQ action in vivo. Exogenous 5-hydroxytryptamine (5-HT) rescued PZQ-evoked polarity and mobility defects in free-living planarian flatworms. In contrast, knockdown of a prevalently expressed planarian 5-HT receptor potentiated or phenocopied PZQ action in different functional assays. Subsequent screening of serotonergic ligands revealed that several ergot alkaloids possessed broad efficacy at modulating regenerative outcomes and the mobility of both free living and parasitic flatworms. Ergot alkaloids that phenocopied PZQ in regenerative assays to cause bipolar regeneration exhibited structural modifications consistent with serotonergic blockade. These data suggest that serotonergic activation blocks PZQ action in vivo, while serotonergic antagonists phenocopy PZQ action. Importantly these studies identify the ergot alkaloid scaffold as a promising structural framework for designing potent agents targeting parasitic bioaminergic G protein coupled receptors. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 9 9 e0004063 |
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 John D Chan Prince N Agbedanu Thomas Grab Mostafa Zamanian Peter I Dosa Timothy A Day Jonathan S Marchant Ergot Alkaloids (Re)generate New Leads as Antiparasitics. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
Praziquantel (PZQ) is a key therapy for treatment of parasitic flatworm infections of humans and livestock, but the mechanism of action of this drug is unresolved. Resolving PZQ-engaged targets and effectors is important for identifying new druggable pathways that may yield novel antiparasitic agents. Here we use functional, genetic and pharmacological approaches to reveal that serotonergic signals antagonize PZQ action in vivo. Exogenous 5-hydroxytryptamine (5-HT) rescued PZQ-evoked polarity and mobility defects in free-living planarian flatworms. In contrast, knockdown of a prevalently expressed planarian 5-HT receptor potentiated or phenocopied PZQ action in different functional assays. Subsequent screening of serotonergic ligands revealed that several ergot alkaloids possessed broad efficacy at modulating regenerative outcomes and the mobility of both free living and parasitic flatworms. Ergot alkaloids that phenocopied PZQ in regenerative assays to cause bipolar regeneration exhibited structural modifications consistent with serotonergic blockade. These data suggest that serotonergic activation blocks PZQ action in vivo, while serotonergic antagonists phenocopy PZQ action. Importantly these studies identify the ergot alkaloid scaffold as a promising structural framework for designing potent agents targeting parasitic bioaminergic G protein coupled receptors. |
format |
Article in Journal/Newspaper |
author |
John D Chan Prince N Agbedanu Thomas Grab Mostafa Zamanian Peter I Dosa Timothy A Day Jonathan S Marchant |
author_facet |
John D Chan Prince N Agbedanu Thomas Grab Mostafa Zamanian Peter I Dosa Timothy A Day Jonathan S Marchant |
author_sort |
John D Chan |
title |
Ergot Alkaloids (Re)generate New Leads as Antiparasitics. |
title_short |
Ergot Alkaloids (Re)generate New Leads as Antiparasitics. |
title_full |
Ergot Alkaloids (Re)generate New Leads as Antiparasitics. |
title_fullStr |
Ergot Alkaloids (Re)generate New Leads as Antiparasitics. |
title_full_unstemmed |
Ergot Alkaloids (Re)generate New Leads as Antiparasitics. |
title_sort |
ergot alkaloids (re)generate new leads as antiparasitics. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2015 |
url |
https://doi.org/10.1371/journal.pntd.0004063 https://doaj.org/article/1f81f024f3a24ffda1ff9ec6c880b22b |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 9, Iss 9, p e0004063 (2015) |
op_relation |
http://europepmc.org/articles/PMC4569474?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0004063 https://doaj.org/article/1f81f024f3a24ffda1ff9ec6c880b22b |
op_doi |
https://doi.org/10.1371/journal.pntd.0004063 |
container_title |
PLOS Neglected Tropical Diseases |
container_volume |
9 |
container_issue |
9 |
container_start_page |
e0004063 |
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1766337809853972480 |