Identification of the nuclear receptor DAF-12 as a therapeutic target in parasitic nematodes.
Proc Natl Acad Sci U S A
; 106(23): 9138-43, 2009 Jun 09.
Article
en En
| MEDLINE
| ID: mdl-19497877
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.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Strongyloides stercoralis
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Infecciones por Strongylida
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Necator americanus
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Receptores Citoplasmáticos y Nucleares
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Ancylostoma
Tipo de estudio:
Diagnostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Año:
2009
Tipo del documento:
Article
País de afiliación:
Estados Unidos