Identification of a nuclear receptor as a therapeutic target in parasitic nematodes
David Mangelsdorf group (University of Texas Southwestern Medical Center) and collaborators
The group of David Mangelsdorf at the University of Texas
Southwestern Medical Center and collaborators recently solved the structure
of the nuclear receptor DAF-12 from the nematode parasite, Strongyloides
stercoralis, and identified nuclear receptors as new therapeutic targets
against parasitic nematodes. Parasitic nematodes affect the health of over
one billion people worldwide. Treatments are unreliable against severe forms
of S. stercoralis infection, and resistance to common treatments is
increasing. The investigators showed that a conserved nuclear hormone
receptor signaling pathway through DAF-12 governs stage 3 infection larvae
(iL3), and that the administration of DAF-12 ligands, steroid hormone-like
dafachronic acids, markedly reduced the pathogenic iL3 population, indicating
the potential use of DAF-12 ligands to treat disseminated strongyloidiasis.
The structure of the DAF-12 ligand-binding domain with a coactivator peptide
and a dafachronic acid may guide development of better therapeutics.
Figure: Crystal structure of the
DAF-12 ligand-binding domain with coactivator peptides (red and salmon) and
the Δ7 ligand.
Wang, Z, Zhou, XE, Motola, DL, Gao, X, Suino-Powell, K, Conneely, A, Ogata,
C, Sharma, KK, Auchus, RJ, Lok, JB, Hawdon, JM, Kliewer, SA, Xu, HE,
Mangelsdorf, DJ. Identification of the nuclear receptor DAF-12 as a
therapeutic target in parasitic nematodes, Proc. Natl. Acad. Sci. USA 106
(23), 9138-9143 (2009). DOI: 10.1073/pnas.0904064106