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

Jolien Souffriau (UGent) , Melanie Eggermont (UGent) , Sara Van Ryckeghem (UGent) , Kelly Van Looveren (UGent) , Lise Van Wyngene (UGent) , Evelien Van Hamme (UGent) , Marnik Vuylsteke (UGent) , Rudi Beyaert (UGent) , Karolien De Bosscher (UGent) and Claude Libert (UGent)
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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.
Keywords
LIGAND-BINDING DOMAIN, IMPROVED THERAPEUTIC INDEX, DNA-BINDING, MOLECULAR-MECHANISMS, DIMERIZATION, CORTIVAZOL, GENE, ACTIVATION, INHIBITION, EXPRESSION

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Chicago
Souffriau, Jolien, Melanie Eggermont, Sara Van Ryckeghem, Kelly Van Looveren, Lise Van Wyngene, Evelien Van Hamme, Marnik Vuylsteke, Rudi Beyaert, Karolien De Bosscher, and Claude Libert. 2018. “A Screening Assay for Selective Dimerizing Glucocorticoid Receptor Agonists and Modulators (SEDIGRAM) That Are Effective Against Acute Inflammation.” Scientific Reports 8.
APA
Souffriau, J., Eggermont, M., Van Ryckeghem, S., Van Looveren, K., Van Wyngene, L., Van Hamme, E., Vuylsteke, M., et al. (2018). A screening assay for Selective Dimerizing Glucocorticoid Receptor Agonists and Modulators (SEDIGRAM) that are effective against acute inflammation. SCIENTIFIC REPORTS, 8.
Vancouver
1.
Souffriau J, Eggermont M, Van Ryckeghem S, Van Looveren K, Van Wyngene L, Van Hamme E, et al. A screening assay for Selective Dimerizing Glucocorticoid Receptor Agonists and Modulators (SEDIGRAM) that are effective against acute inflammation. SCIENTIFIC REPORTS. 2018;8.
MLA
Souffriau, Jolien, Melanie Eggermont, Sara Van Ryckeghem, et al. “A Screening Assay for Selective Dimerizing Glucocorticoid Receptor Agonists and Modulators (SEDIGRAM) That Are Effective Against Acute Inflammation.” SCIENTIFIC REPORTS 8 (2018): n. pag. Print.
@article{8582943,
  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.},
  articleno    = {12894},
  author       = {Souffriau, Jolien and Eggermont, Melanie and Van Ryckeghem, Sara and Van Looveren, Kelly and Van Wyngene, Lise and Van Hamme, Evelien and Vuylsteke, Marnik and Beyaert, Rudi and De Bosscher, Karolien and Libert, Claude},
  issn         = {2045-2322},
  journal      = {SCIENTIFIC REPORTS},
  language     = {eng},
  pages        = {13},
  title        = {A screening assay for Selective Dimerizing Glucocorticoid Receptor Agonists and Modulators (SEDIGRAM) that are effective against acute inflammation},
  url          = {http://dx.doi.org/10.1038/s41598-018-31150-w},
  volume       = {8},
  year         = {2018},
}

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