Coalescing beneficial host and deleterious antiparasitic actions as an antischistosomal strategy

Abstract
Data availability
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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.

The following data sets were generated

(2018) RNA-Seq of schistosome infected mus musculus: adult female liver
SRP131511.

https://www.ncbi.nlm.nih.gov/sra/SRP131511

Article and author information

Author details

John D Chan

Department of Biomedical Sciences, Iowa State University, Ames, United States

Competing interests
The authors declare that no competing interests exist.
Timothy A Day

Department of Biomedical Sciences, Iowa State University, Ames, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-9037-6540
Jonathan S Marchant

Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, United States

For correspondence
JMarchant@mcw.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-6592-0877

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

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.