Didiot, Marie-Cecile, Agarinis, Claudia, Varin, Thibault, Wu, Hua, Nelson, Thomas, Selinger, Douglas, King, Frederick, Schuffenhauer, Ansgar and Parker, Christian (2013) Glucocorticoid receptor ligands modulate EMCV Internal Ribosome Entry Site Activity. ASSAY and Drug Development Technologies, 11 (6). pp. 355-366.

Abstract

The use of small molecules to modulate cellular processes is a powerful approach to investigate gene function as a complement to genetic approaches. The discovery and characterization of compounds that modulate translation initiation, the rate-limiting step of protein synthesis, is important both to provide tool compounds to explore this fundamental biological process and to further evaluate protein synthesis as a therapeutic target. While most mRNAs recruit ribosomes via their 5’ cap, some viral and cellular mRNAs initiate protein synthesis via an alternative “cap-independent” mechanism utilizing IRES elements. IRES elements are complex structures, localized within the 5’ non-translated region of the mRNA upstream of the AUG start codon. This report described the design of a functional, high throughput screen of small molecules miniaturized into a 1536-well format and performed using the luciferase reporter gene under control of the viral EMCV IRES element to identify non toxic compounds modulating translation initiated from the EMCV IRES. One activating compound, validated in a dose response manner, has previously been shown to bind the glucocorticoid receptor. Subsequent testing of additional glucocorticoid receptors modulators further supported this as the possible mechanism of action. Detailed characterization of this compound activity supported the notion that this was due to an effect at the level of translation.

Item Type:	Article
Keywords:	Glucocorticoid receptor, IRES element, EMCV IRES
Date Deposited:	26 Apr 2016 23:46
Last Modified:	26 Apr 2016 23:46
URI:	https://oak.novartis.com/id/eprint/9613