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...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2018-07-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/35755 |
| _version_ | 1811199386847281152 |
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| author | John D Chan Timothy A Day Jonathan S Marchant |
| author_facet | John D Chan Timothy A Day Jonathan S Marchant |
| author_sort | John D Chan |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-12T01:47:28Z |
| format | Article |
| id | doaj.art-9ca3f489911f433e8dfe45d21f94a1ca |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T01:47:28Z |
| publishDate | 2018-07-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-9ca3f489911f433e8dfe45d21f94a1ca2022-12-22T03:53:02ZengeLife Sciences Publications LtdeLife2050-084X2018-07-01710.7554/eLife.35755Coalescing beneficial host and deleterious antiparasitic actions as an antischistosomal strategyJohn D Chan0https://orcid.org/0000-0003-4986-972XTimothy A Day1https://orcid.org/0000-0002-9037-6540Jonathan S Marchant2https://orcid.org/0000-0001-6592-0877Department of Biomedical Sciences, Iowa State University, Ames, United StatesDepartment of Biomedical Sciences, Iowa State University, Ames, United StatesDepartment of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, United StatesConventional 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.https://elifesciences.org/articles/35755schistosomiasisparasitic diseasesG protein coupled receptordrug discovery |
| spellingShingle | John D Chan Timothy A Day Jonathan S Marchant Coalescing beneficial host and deleterious antiparasitic actions as an antischistosomal strategy eLife schistosomiasis parasitic diseases G protein coupled receptor drug discovery |
| 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 | schistosomiasis parasitic diseases G protein coupled receptor drug discovery |
| url | https://elifesciences.org/articles/35755 |
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