A screening assay for Selective Dimerizing Glucocorticoid Receptor Agonists and Modulators (SEDIGRAM) that are effective against acute inflammation

Scientific Reports
Jolien SouffriauClaude Libert

Abstract

It has been suggested that glucocorticoid receptor (GR) agonists that promote GR homodimerization more than standard glucocorticoids such as Dexamethasone could be more effective anti-inflammatory molecules against acute and life-threatening inflammatory conditions. To test this hypothesis, we set up a screening pipeline aimed at discovering such Selective Dimerizing GR Agonists and Modulators (SEDIGRAM). The pipeline consists of a reporter gene assay based on a palindromic glucocorticoid responsive element (GRE). This assay represents GR dimerization in human A549 lung epithelial cells. In the pipeline, this is followed by analysis of endogenous GRE-driven gene expression, a FRET assay confirming dimerization, and monitoring of in vitro and in vivo anti-inflammatory activity. In a proof of principle experiment, starting from seven candidate compounds, we identified two potentially interesting compounds (Cortivazol and AZD2906) that confer strong protection in a mouse model of aggressive TNF-induced lethal inflammation. A screening pipeline for SEDIGRAM may assist the search for compounds that promote GR dimerization and limit overwhelming acute inflammatory responses.

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Citations

Aug 24, 2019·Frontiers in Immunology·Laura Escoter-TorresSabine Vettorazzi
Dec 29, 2018·International Journal of Molecular Sciences·Aikaterini G KarraAnna-Maria G Psarra
Nov 2, 2018·European Journal of Medicinal Chemistry·Eduard BadarauLéon Ghosez
Nov 1, 2020·Archives of Biochemistry and Biophysics·Aikaterini G KarraAnna-Maria G Psarra
Mar 22, 2021·The Journal of Biological Chemistry·Claire C MunierMatthew W D Perry

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Methods Mentioned

BETA
transgenic
Fluorescence
FRET
sedation
ELISA

Software Mentioned

SEDIGRAM
Fosdagrocorat
Mapracorat
GraphPad
Graphpad Prism
SEMOGRAM
geNorm Housekeeping Gene Selection
Genstat

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