Synthetic DAF-12 modulators with potential use in controlling the nematode life cycle

Dafachronic acids (DAs) are 3-keto cholestenoic 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 p...

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Autores principales:	Dansey, M.V., Alvarez, L.D., Samaja, G., Escudero, D.S., Veleiro, A.S., Pecci, A., Castro, O.A., Burton, G.
Formato:	JOUR
Materias:	Caenorhabditis elegans DAF-12 receptor Daf-9 mutant Dafachronic acid Molecular dynamics 24 hydroxy 4 cholen 3 one alcohol derivative carboxylic acid derivative dafachronic acid receptor 12 steroid unclassified drug Caenorhabditis elegans protein cell receptor cholestane derivative DAF-12 protein, C elegans dafachronic acid ligand animal experiment Article biological activity concentration response conformation controlled study developmental stage HEK293 cell line human human cell in vitro study in vivo study life cycle luciferase assay nonhuman phenotype quantum chemistry transactivation allele animal chemistry drug effects growth, development and aging life cycle stage metabolism reporter gene Nematoda Alleles Animals Caenorhabditis elegans Proteins Cholestenes Genes, Reporter HEK293 Cells Humans Life Cycle Stages Ligands Receptors, Cytoplasmic and Nuclear
Acceso en línea:	http://hdl.handle.net/20.500.12110/paper_02646021_v465_n_p175_Dansey
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

id	todo:paper_02646021_v465_n_p175_Dansey
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spelling	todo:paper_02646021_v465_n_p175_Dansey2023-10-03T15:13:03Z Synthetic DAF-12 modulators with potential use in controlling the nematode life cycle Dansey, M.V. Alvarez, L.D. Samaja, G. Escudero, D.S. Veleiro, A.S. Pecci, A. Castro, O.A. Burton, G. Caenorhabditis elegans DAF-12 receptor Daf-9 mutant Dafachronic acid Molecular dynamics 24 hydroxy 4 cholen 3 one alcohol derivative carboxylic acid derivative dafachronic acid receptor 12 steroid unclassified drug Caenorhabditis elegans protein cell receptor cholestane derivative DAF-12 protein, C elegans dafachronic acid ligand animal experiment Article biological activity Caenorhabditis elegans concentration response conformation controlled study developmental stage HEK293 cell line human human cell in vitro study in vivo study life cycle luciferase assay nonhuman phenotype quantum chemistry transactivation allele animal Caenorhabditis elegans chemistry drug effects growth, development and aging life cycle stage metabolism reporter gene Caenorhabditis elegans Nematoda Alleles Animals Caenorhabditis elegans Caenorhabditis elegans Proteins Cholestenes Genes, Reporter HEK293 Cells Humans Life Cycle Stages Ligands Receptors, Cytoplasmic and Nuclear Dafachronic acids (DAs) are 3-keto cholestenoic 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) Caenorhabditis elegans mutants. In the present paper, to investigate further the relationship between the structure of the steroid side chain and 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, whereas 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. © The Authors Journal compilation © 2015 Biochemical Society. Fil:Dansey, M.V. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Veleiro, A.S. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Pecci, A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Castro, O.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Burton, G. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_02646021_v465_n_p175_Dansey
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic	Caenorhabditis elegans DAF-12 receptor Daf-9 mutant Dafachronic acid Molecular dynamics 24 hydroxy 4 cholen 3 one alcohol derivative carboxylic acid derivative dafachronic acid receptor 12 steroid unclassified drug Caenorhabditis elegans protein cell receptor cholestane derivative DAF-12 protein, C elegans dafachronic acid ligand animal experiment Article biological activity Caenorhabditis elegans concentration response conformation controlled study developmental stage HEK293 cell line human human cell in vitro study in vivo study life cycle luciferase assay nonhuman phenotype quantum chemistry transactivation allele animal Caenorhabditis elegans chemistry drug effects growth, development and aging life cycle stage metabolism reporter gene Caenorhabditis elegans Nematoda Alleles Animals Caenorhabditis elegans Caenorhabditis elegans Proteins Cholestenes Genes, Reporter HEK293 Cells Humans Life Cycle Stages Ligands Receptors, Cytoplasmic and Nuclear
spellingShingle	Caenorhabditis elegans DAF-12 receptor Daf-9 mutant Dafachronic acid Molecular dynamics 24 hydroxy 4 cholen 3 one alcohol derivative carboxylic acid derivative dafachronic acid receptor 12 steroid unclassified drug Caenorhabditis elegans protein cell receptor cholestane derivative DAF-12 protein, C elegans dafachronic acid ligand animal experiment Article biological activity Caenorhabditis elegans concentration response conformation controlled study developmental stage HEK293 cell line human human cell in vitro study in vivo study life cycle luciferase assay nonhuman phenotype quantum chemistry transactivation allele animal Caenorhabditis elegans chemistry drug effects growth, development and aging life cycle stage metabolism reporter gene Caenorhabditis elegans Nematoda Alleles Animals Caenorhabditis elegans Caenorhabditis elegans Proteins Cholestenes Genes, Reporter HEK293 Cells Humans Life Cycle Stages Ligands Receptors, Cytoplasmic and Nuclear Dansey, M.V. Alvarez, L.D. Samaja, G. Escudero, D.S. Veleiro, A.S. Pecci, A. Castro, O.A. Burton, G. Synthetic DAF-12 modulators with potential use in controlling the nematode life cycle
topic_facet	Caenorhabditis elegans DAF-12 receptor Daf-9 mutant Dafachronic acid Molecular dynamics 24 hydroxy 4 cholen 3 one alcohol derivative carboxylic acid derivative dafachronic acid receptor 12 steroid unclassified drug Caenorhabditis elegans protein cell receptor cholestane derivative DAF-12 protein, C elegans dafachronic acid ligand animal experiment Article biological activity Caenorhabditis elegans concentration response conformation controlled study developmental stage HEK293 cell line human human cell in vitro study in vivo study life cycle luciferase assay nonhuman phenotype quantum chemistry transactivation allele animal Caenorhabditis elegans chemistry drug effects growth, development and aging life cycle stage metabolism reporter gene Caenorhabditis elegans Nematoda Alleles Animals Caenorhabditis elegans Caenorhabditis elegans Proteins Cholestenes Genes, Reporter HEK293 Cells Humans Life Cycle Stages Ligands Receptors, Cytoplasmic and Nuclear
description	Dafachronic acids (DAs) are 3-keto cholestenoic 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) Caenorhabditis elegans mutants. In the present paper, to investigate further the relationship between the structure of the steroid side chain and 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, whereas 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. © The Authors Journal compilation © 2015 Biochemical Society.
format	JOUR
author	Dansey, M.V. Alvarez, L.D. Samaja, G. Escudero, D.S. Veleiro, A.S. Pecci, A. Castro, O.A. Burton, G.
author_facet	Dansey, M.V. Alvarez, L.D. Samaja, G. Escudero, D.S. Veleiro, A.S. Pecci, A. Castro, O.A. Burton, G.
author_sort	Dansey, M.V.
title	Synthetic DAF-12 modulators with potential use in controlling the nematode life cycle
title_short	Synthetic DAF-12 modulators with potential use in controlling the nematode life cycle
title_full	Synthetic DAF-12 modulators with potential use in controlling the nematode life cycle
title_fullStr	Synthetic DAF-12 modulators with potential use in controlling the nematode life cycle
title_full_unstemmed	Synthetic DAF-12 modulators with potential use in controlling the nematode life cycle
title_sort	synthetic daf-12 modulators with potential use in controlling the nematode life cycle
url	http://hdl.handle.net/20.500.12110/paper_02646021_v465_n_p175_Dansey
work_keys_str_mv	AT danseymv syntheticdaf12modulatorswithpotentialuseincontrollingthenematodelifecycle AT alvarezld syntheticdaf12modulatorswithpotentialuseincontrollingthenematodelifecycle AT samajag syntheticdaf12modulatorswithpotentialuseincontrollingthenematodelifecycle AT escuderods syntheticdaf12modulatorswithpotentialuseincontrollingthenematodelifecycle AT veleiroas syntheticdaf12modulatorswithpotentialuseincontrollingthenematodelifecycle AT peccia syntheticdaf12modulatorswithpotentialuseincontrollingthenematodelifecycle AT castrooa syntheticdaf12modulatorswithpotentialuseincontrollingthenematodelifecycle AT burtong syntheticdaf12modulatorswithpotentialuseincontrollingthenematodelifecycle
_version_	1782024114370772992

Synthetic DAF-12 modulators with potential use in controlling the nematode life cycle

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