Coalescing beneficial host and deleterious antiparasitic actions as an antischistosomal strategy
- Iowa State University, United States
- Medical College of Wisconsin, United States
Abstract
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.
Data availability
RNA-Seq data has been deposited in the NCBI SRA database under accession number SRP131511.
Article and author information
Author details
Jonathan S Marchant
Funding
National Institutes of Health (R21AI25821)
- Jonathan S Marchant
National Institutes of Health (R21AI130642)
- Jonathan S Marchant
National Institutes of Health (R01GM088790)
- Jonathan S Marchant
National Institutes of Health (F32AI124598)
- John D Chan
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal experiments followed ethical regulations approved by the Medical College of Wisconsin IACUC committee (AUA00006079) and additionally reviewed in the context of extramural funding by the National Institutes of Health (NIAID).
Copyright
© 2018, Chan et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Coalescing beneficial host and deleterious antiparasitic actions as an antischistosomal strategy
eLife 7:e35755.
https://doi.org/10.7554/eLife.35755
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