Format

Send to

Choose Destination
J Steroid Biochem Mol Biol. 2020 Jan 10;199:105585. doi: 10.1016/j.jsbmb.2020.105585. [Epub ahead of print]

Cholestenoic acid analogues as inverse agonists of the liver X receptors.

Author information

1
Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de Química Biológica, Buenos Aires, Argentina; CONICET-Universidad de Buenos Aires, UMYMFOR, Buenos Aires, Argentina.
2
CONICET-Universidad de Buenos Aires, IFIBYNE, Buenos Aires, Argentina.
3
Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de Química Orgánica, Buenos Aires, Argentina; CONICET-Universidad de Buenos Aires, UMYMFOR, Buenos Aires, Argentina.
4
Pamgene International BV, 5211 HH Den Bosch, The Netherlands.
5
CONICET-Universidad de Buenos Aires, UMYMFOR, Buenos Aires, Argentina.
6
Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de Química Biológica, Buenos Aires, Argentina; CONICET-Universidad de Buenos Aires, IFIBYNE, Buenos Aires, Argentina.
7
Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de Química Orgánica, Buenos Aires, Argentina; CONICET-Universidad de Buenos Aires, UMYMFOR, Buenos Aires, Argentina. Electronic address: burton@qo.fcen.uba.ar.

Abstract

Liver X Receptors (LXRs) are ligand dependent transcription factors activated by oxidized cholesterol metabolites (oxysterols) that play fundamental roles in the transcriptional control of lipid metabolism, cholesterol transport and modulation of inflammatory responses. In the last decade, LXRs have become attractive pharmacological targets for intervention in human metabolic diseases and thus, several efforts have concentrated on the development of synthetic analogues able to modulate LXR transcriptional response. In this sense, we have previously found that cholestenoic acid analogues with a modified side chain behave as LXR inverse agonists. To further investigate the structure-activity relationships and to explore how cholestenoic acid derivatives interact with the LXRs, we evaluated the LXR biological activity of new analogues containing a C24-C25 double bond. Furthermore, a microarray assay was performed to evaluate the recruitment of coregulators to recombinant LXR LBD upon ligand binding. Also, conventional and accelerated molecular dynamics simulations were applied to gain insight on the molecular determinants involved in the inverse agonism. As LXR inverse agonists emerge as very promising candidates to control LXR activity, the cholestenoic acid analogues here depicted constitute a new relevant steroidal scaffold to inhibit LXR action.

KEYWORDS:

Coregulators; Inverse agonists; Liver X receptor; Molecular dynamics simulation

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center