UMYMFOR   05516
UNIDAD DE MICROANALISIS Y METODOS FISICOS EN QUIMICA ORGANICA
Unidad Ejecutora - UE
artículos
Título:
Synthetic DAF-12 modulators with potential use in controlling nematodes life cycle
Autor/es:
DAMSEY MV; ALVAREZ LD; SAMAJA GA; ESCUDERO D; VELEIRO AS; PECCI A; CASTRO OA.; BURTON G
Revista:
BIOCHEMICAL JOURNAL
Editorial:
PORTLAND PRESS LTD
Referencias:
Lugar: Londres; Año: 2014 vol. 465 p. 175 - 184
ISSN:
0264-6021
Resumen:
Synthetic DAF-12 modulators with potential use in controlling nematodes life cycle. Dansey MV, Alvarez LD, Samaja G, Escudero DS, Veleiro AS, Pecci A, Castro OA, Burton G. Abstract Dafachronic acids (DAs) are 3-keto colestenoic acids bearing a carboxylic acid moiety at the end of the steroid side chain. These compounds interact with the DAF-12 receptor, a ligand dependent transcription factor that acts as a molecular switch mediating the choice between arrest at diapause or progression to reproductive development and adult lifespan in different nematodes. Recently, we reported that the 27-nor-Δ4-DA, was able to directly activate DAF-12 in a transactivation cell-based luciferase assay and rescued the Mig phenotype of daf-9(rh50) C. elegans mutants. Here, to further investigate the relationship between the structure of the steroid side chain and the DAF-12 activity, we evaluated the in vitro and in vivo activity of Δ4-DA analogues with modified side chains using transactivation cell based assays and daf-9(dh6) C. elegans mutants. Our results revealed that introduction of a 24,25 double bond on the cholestenoic acid side chain did not affect DAF-12 activity while shortening the side chain lowered the activity. Most interestingly, the C24 alcohol 24-hydroxy-4-cholen-3-one (6) was an antagonist of the DAF-12 receptor both in vitro and in vivo.