UMYMFOR   05516
UNIDAD DE MICROANALISIS Y METODOS FISICOS EN QUIMICA ORGANICA
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Cholestenoic Acid Analogues as Inverse Agonists of the Liver X Receptor
Autor/es:
PEÑA, C. I.; BURTON, G.; ALVAREZ, L. D.; VELEIRO, A. S.; DANSEY, M. V.; PECCI, A.
Lugar:
Bariloche
Reunión:
Simposio; 4th South American Symposium in Signal Transduction and Molecular Medicine; 2018
Institución organizadora:
SISTAM
Resumen:
The Liver X Receptors are ligand regulated transcription factors belonging to thenuclear receptor (NR) family. They are involved in numerous relevant physiologicalfunctions, such as cholesterol, lipid and glucose homeostasis and inflammation. Theaccumulated evidence suggests that modulation of LXRs through the use of specificligands might be beneficial for the treatment of several affections, such as theAlzheimer?s disease, atherosclerosis and cancer. In this sense, putative therapeuticuses were proposed for both LXR activating and repressing compounds.Previously we found that the elimination of the 25-methyl group of the cholestenoicacid, a natural LXR agonist, drastically altered the LXR activity. With the goal toextend the study of the cholestenoic acid analogue ìs structure-activity relationship,we prepared compounds in which an unsaturation between carbons C24 and C25was introduced. Results from reporter gene assays showed that the LXR activityclearly depends on the configuration of the double bond. Moreover, by using acoregulator recruitment micro-array assay we evaluated the ability of thecompounds to induce receptor binding to peptides containing diverse NR boxes.Finally, by carrying out conventional and accelerated MD simulations we have gainedinsight in the molecular determinants involved in ligand action. Our results indicatethat inverse agonists achieve a receptor state completely different from thatachieved by full agonists. Inverse agonists withdraw the receptor from the minimalenergy agonist state to other states with a more flexible H12, altering the interactionwith certain NR-boxes and consequently leading to a receptor state able to betterrecruit corepresors than coactivators.Non-steroidal inverse agonists have been described with potential medicalapplications. Thus, inverse agonists emerge as very promising candidates to controlthe LXR activity, constituting the cholestenoic acid analogues a new steroidalscaffold.