1. Identification of the nuclear receptor DAF-12 as a therapeutic target in parasitic nematodes
- Author
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Wang, Zhu, Zhou, X. Edward, Motola, Daniel L., Gao, Xin, Suino-Powell, Kelly, Conneely, Aoife, Ogata, Craig, Sharma, Kamalesh K., Auchus, Richard J., Lok, James B., Hawdon, John M., Kliewer, Steven A., Xu, H. Eric, and Mangelsdorf, David J.
- Subjects
Hormone receptors -- Properties ,Roundworm infections -- Physiological aspects ,Roundworm infections -- Drug therapy ,Nematoda -- Physiological aspects ,Pharmacology -- Research ,Science and technology - Abstract
Nematode parasitism is a worldwide health problem resulting in malnutrition and morbidity in over I billion people. The molecular mechanisms governing infection are poorly understood. Here, we report that an evolutionarily conserved nuclear hormone receptor signaling pathway governs development of the stage 3 infective larvae (iL3) in several nematode parasites, including Strongyloides stercoralis, Ancylostoma spp., and Necator americanus. As in the free-living Caenorhabditis elegans, steroid hormone-like dafachronic acids induced recovery of the dauer-like iL3 in parasitic nematodes by activating orthologs of the nuclear receptor DAF-12. Moreover, administration of dafachronic acid markedly reduced the pathogenic iL3 population in S. stercoralis, indicating the potential use of DAF-12 ligands to treat disseminated strongyloidiasis. To understand the pharmacology of targeting DAF-12, we solved the 3-dimensional structure of the S. stercoralis DAF-12 ligand-binding domain cocrystallized with dafachronic acids. These results reveal the molecular basis for DAF-12 ligand binding and identify nuclear receptors as unique therapeutic targets in parasitic nematodes. dafachronic acid | parasitology | pharmacology | X-ray crystal structure
- Published
- 2009