Abstract | BACKGROUND: METHODOLOGY/PRINCIPAL FINDINGS: A phenotypic screen involving Schistosoma mansoni and 1,085 benzoxaboroles identified a subset of huPDE4 inhibitors that induced parasite hypermotility and degeneration. To uncover the putative schistosome PDE4 target, we characterized four PDE4 sequences (SmPDE4A-D) in the parasite's genome and transcriptome, and cloned and recombinantly expressed the catalytic domain of SmPDE4A. Among a set of benzoxaboroles and catechol inhibitors that differentially inhibit huPDE4, a relationship between the inhibition of SmPDE4A, and parasite hypermotility and degeneration, was measured. To validate SmPDE4A as the benzoxaborole molecular target, we first generated Caenorhabditis elegans lines that express a cDNA for smpde4a on a pde4(ce268) mutant (hypermotile) background: the smpde4a transgene restored mutant worm motility to that of the wild type. We then showed that benzoxaborole inhibitors of SmPDE4A that induce hypermotility in the schistosome also elicit a hypermotile response in the C. elegans lines that express the smpde4a transgene, thereby confirming SmPDE4A as the relevant target. CONCLUSIONS/SIGNIFICANCE: The orthogonal chemical, biological and genetic strategies employed identify SmPDE4A's contribution to parasite motility and degeneration, and its potential as a drug target. Transgenic C. elegans is highlighted as a potential screening tool to optimize small molecule chemistries to flatworm molecular drug targets.
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Authors | Thavy Long, Liliana Rojo-Arreola, Da Shi, Nelly El-Sakkary, Kurt Jarnagin, Fernando Rock, Maliwan Meewan, Alberto A Rascón Jr, Lin Lin, Katherine A Cunningham, George A Lemieux, Larissa Podust, Ruben Abagyan, Kaveh Ashrafi, James H McKerrow, Conor R Caffrey |
Journal | PLoS neglected tropical diseases
(PLoS Negl Trop Dis)
Vol. 11
Issue 7
Pg. e0005680
(Jul 2017)
ISSN: 1935-2735 [Electronic] United States |
PMID | 28704396
(Publication Type: Journal Article)
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Chemical References |
- Anthelmintics
- Phosphodiesterase 4 Inhibitors
- Cyclic Nucleotide Phosphodiesterases, Type 4
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Topics |
- Animals
- Animals, Genetically Modified
(genetics)
- Anthelmintics
(pharmacology)
- Caenorhabditis elegans
(drug effects, genetics)
- Catalytic Domain
- Cloning, Molecular
- Cyclic Nucleotide Phosphodiesterases, Type 4
(genetics, metabolism)
- Locomotion
(drug effects)
- Phosphodiesterase 4 Inhibitors
(pharmacology)
- Schistosoma mansoni
(anatomy & histology, drug effects, physiology)
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