Identification of the nuclear receptor DAF-12 as a therapeutic target in parasitic nematodes

Zhu Wang, X. Edward Zhou, Daniel L. Motola, Xin Gao, Kelly Suino-Powell, Aoife Conneely, Craig Ogata, Kamalesh K. Sharma, Richard J. Auchus, James B. Lok, John M. Hawdon, Steven A. Kliewer, H. Eric Xu, David J. Mangelsdorf

Research output: Contribution to journalArticle

84 Scopus citations

Abstract

Nematode parasitism is a worldwide health problem resulting in malnutrition and morbidity in over 1 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.

Original languageEnglish (US)
Pages (from-to)9138-9143
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number23
DOIs
StatePublished - Jun 9 2009

Keywords

  • Dafachronic acid
  • Parasitology
  • Pharmacology
  • X-ray crystal structure

ASJC Scopus subject areas

  • General

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    Wang, Z., Zhou, X. E., Motola, D. L., Gao, X., Suino-Powell, K., Conneely, A., Ogata, C., Sharma, K. K., Auchus, R. J., Lok, J. B., Hawdon, J. M., Kliewer, S. A., Xu, H. E., & Mangelsdorf, D. J. (2009). Identification of the nuclear receptor DAF-12 as a therapeutic target in parasitic nematodes. Proceedings of the National Academy of Sciences of the United States of America, 106(23), 9138-9143. https://doi.org/10.1073/pnas.0904064106