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Coalescing beneficial host and deleterious antiparasitic actions as an antischistosomal strategy

Conventional approaches for antiparasitic drug discovery center upon discovering selective agents that adversely impact parasites with minimal host side effects. Here, we show that agents with a broad polypharmacology, often considered ‘dirtier’ drugs, can have unique efficacy if they combine delete...

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Detalles Bibliográficos
Autores principales: Chan, John D, Day, Timothy A, Marchant, Jonathan S
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6095690/
https://www.ncbi.nlm.nih.gov/pubmed/30059006
http://dx.doi.org/10.7554/eLife.35755
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author Chan, John D
Day, Timothy A
Marchant, Jonathan S
author_facet Chan, John D
Day, Timothy A
Marchant, Jonathan S
author_sort Chan, John D
collection PubMed
description Conventional approaches for antiparasitic drug discovery center upon discovering selective agents that adversely impact parasites with minimal host side effects. Here, we show that agents with a broad polypharmacology, often considered ‘dirtier’ drugs, can have unique efficacy if they combine deleterious effects on the parasite with beneficial actions in the host. This principle is evidenced through a screen for drugs to treat schistosomiasis, a parasitic flatworm disease that impacts over 230 million people. A target-based screen of a Schistosoma serotoninergic G protein coupled receptor yielded the potent agonist, ergotamine, which disrupted worm movement. In vivo, ergotamine decreased mortality, parasite load and intestinal egg counts but also uniquely reduced organ pathology through engagement of host GPCRs that repressed hepatic stellate cell activation, inflammatory damage and fibrosis. The unique ability of ergotamine to engage both host and parasite GPCRs evidences a future strategy for anthelmintic drug design that coalesces deleterious antiparasitic activity with beneficial host effects.
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spelling pubmed-60956902018-08-20 Coalescing beneficial host and deleterious antiparasitic actions as an antischistosomal strategy Chan, John D Day, Timothy A Marchant, Jonathan S eLife Cell Biology Conventional approaches for antiparasitic drug discovery center upon discovering selective agents that adversely impact parasites with minimal host side effects. Here, we show that agents with a broad polypharmacology, often considered ‘dirtier’ drugs, can have unique efficacy if they combine deleterious effects on the parasite with beneficial actions in the host. This principle is evidenced through a screen for drugs to treat schistosomiasis, a parasitic flatworm disease that impacts over 230 million people. A target-based screen of a Schistosoma serotoninergic G protein coupled receptor yielded the potent agonist, ergotamine, which disrupted worm movement. In vivo, ergotamine decreased mortality, parasite load and intestinal egg counts but also uniquely reduced organ pathology through engagement of host GPCRs that repressed hepatic stellate cell activation, inflammatory damage and fibrosis. The unique ability of ergotamine to engage both host and parasite GPCRs evidences a future strategy for anthelmintic drug design that coalesces deleterious antiparasitic activity with beneficial host effects. eLife Sciences Publications, Ltd 2018-07-30 /pmc/articles/PMC6095690/ /pubmed/30059006 http://dx.doi.org/10.7554/eLife.35755 Text en © 2018, Chan et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Cell Biology
Chan, John D
Day, Timothy A
Marchant, Jonathan S
Coalescing beneficial host and deleterious antiparasitic actions as an antischistosomal strategy
title Coalescing beneficial host and deleterious antiparasitic actions as an antischistosomal strategy
title_full Coalescing beneficial host and deleterious antiparasitic actions as an antischistosomal strategy
title_fullStr Coalescing beneficial host and deleterious antiparasitic actions as an antischistosomal strategy
title_full_unstemmed Coalescing beneficial host and deleterious antiparasitic actions as an antischistosomal strategy
title_short Coalescing beneficial host and deleterious antiparasitic actions as an antischistosomal strategy
title_sort coalescing beneficial host and deleterious antiparasitic actions as an antischistosomal strategy
topic Cell Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6095690/
https://www.ncbi.nlm.nih.gov/pubmed/30059006
http://dx.doi.org/10.7554/eLife.35755
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