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Coalescing beneficial host and deleterious antiparasitic actions as an antischistosomal strategy. Elife 2018 07 30;7

Date

07/31/2018

Pubmed ID

30059006

Pubmed Central ID

PMC6095690

DOI

10.7554/eLife.35755

Scopus ID

2-s2.0-85052114714   6 Citations

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.

Author List

Chan JD, Day TA, Marchant JS

Author

Jonathan S. Marchant PhD Chair, Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Amino Acid Sequence
Animals
Antiparasitic Agents
Antiprotozoal Agents
Biological Products
Cyclic AMP
Ergotamine
Female
Genes, Reporter
HEK293 Cells
Hepatic Stellate Cells
High-Throughput Screening Assays
Host-Parasite Interactions
Humans
Ligands
Liver
Mice
Phylogeny
Receptors, Serotonin
Reproducibility of Results
Schistosoma mansoni
Schistosomiasis mansoni
Structure-Activity Relationship
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a