Suppression of inflammation by a synthetic histone mimic
Edwige Nicodeme1,7, Kate L. Jeffrey2,7, Uwe Schaefer2,7, Soren Beinke3,7, Scott Dewell4, Chun-wa Chung5, Rohit Chandwani2, Ivan Marazzi2, Paul Wilson5, Hervé Coste1, Julia White5, Jorge Kirilovsky1, Charles M. Rice6, Jose M. Lora3, Rab K. Prinjha3, Kevin Lee3 & Alexander Tarakhovsky2
Centre de Recherche GSK, 27 Avenue du Québec, 91140 Villebon Sur Yvette, France
Laboratory of Lymphocyte Signaling, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA
Epinova DPU, Immuno-Inflammation Centre of Excellence for Drug Discovery, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK
Genomics Resource Center, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA
GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK
Laboratory of Virology and Infectious Disease, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA
These authors contributed equally to this work.
Correspondence to: Alexander Tarakhovsky2 Email: firstname.lastname@example.org
Correspondence to: Kevin Lee3 Email: Kevin.2.Lee@gsk.com
Interaction of pathogens with cells of the immune system results in activation of inflammatory gene expression. This response, although vital for immune defence, is frequently deleterious to the host due to the exaggerated production of inflammatory proteins. The scope of inflammatory responses reflects the activation state of signalling proteins upstream of inflammatory genes as well as signal-induced assembly of nuclear chromatin complexes that support mRNA expression1, 2, 3, 4. Recognition of post-translationally modified histones by nuclear proteins that initiate mRNA transcription and support mRNA elongation is a critical step in the regulation of gene expression5, 6, 7, 8, 9, 10. Here we present a novel pharmacological approach that targets inflammatory gene expression by interfering with the recognition of acetylated histones by the bromodomaine and extra terminal domain (BET) family of proteins. We describe a synthetic compound (I-BET) that by ‘mimicking’ acetylated histones disrupts chromatin complexes responsible for the expression of key inflammatory genes in activated macrophages, and confers protection against lipopolysaccharide-induced endotoxic shock and bacteria-induced sepsis. Our findings suggest that synthetic compounds specifically targeting proteins that recognize post-translationally modified histones can serve as a new generation of immunomodulatory drugs.