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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...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2018
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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. |
format | Online Article Text |
id | pubmed-6095690 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
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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