Coalescing beneficial host and deleterious antiparasitic actions as an antischistosomal strategy. Elife 2018 07 30;7
Date
07/31/2018Pubmed ID
30059006Pubmed Central ID
PMC6095690DOI
10.7554/eLife.35755Scopus ID
2-s2.0-85052114714 6 CitationsAbstract
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 JSAuthor
Jonathan S. Marchant PhD Chair, Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Amino Acid SequenceAnimals
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
