Using systems medicine to identify a therapeutic agent with potential for repurposing in inflammatory bowel disease.

Kate Lloyd ,Chris Probert,Madeleine Kittner,Hazel England,Vladimir Poroikov,Philip Stegmaier,Vítor A P Martins Dos Santos ,Werner Müller ,Barry J Campbell ,Lorna Morris,Carrie A Duckworth ,Emily Smith,Σταματια Παπουτσοπουλου ,David G Spiller ,Alexander Kel,D Mark Pritchard ,Mike White ,François Bergey ,Michael D Burkitt

doi:10.1242/dmm.044040

Abstract

ABSTRACTInflammatory bowel diseases (IBDs) cause significant morbidity and mortality. Aberrant NF-κB signalling is strongly associated with these conditions, and several established drugs influence the NF-κB signalling network to exert their effect. This study aimed to identify drugs that alter NF-κB signalling and could be repositioned for use in IBD. The SysmedIBD Consortium established a novel drug-repurposing pipeline based on a combination of in silico drug discovery and biological assays targeted at demonstrating an impact on NF-κB signalling, and a murine model of IBD. The drug discovery algorithm identified several drugs already established in IBD, including corticosteroids. The highest-ranked drug was the macrolide antibiotic clarithromycin, which has previously been reported to have anti-inflammatory effects in aseptic conditions. The effects of clarithromycin effects were validated in several experiments: it influenced NF-κB-mediated transcription in murine peritoneal macrophages and intestinal enteroids; it suppressed NF-κB protein shuttling in murine reporter enteroids; it suppressed NF-κB (p65) DNA binding in the small intestine of mice exposed to lipopolysaccharide; and it reduced the severity of dextran sulphate sodium-induced colitis in C57BL/6 mice. Clarithromycin also suppressed NF-κB (p65) nuclear translocation in human intestinal enteroids. These findings demonstrate that in silico drug repositioning algorithms can viably be allied to laboratory validation assays in the context of IBD, and that further clinical assessment of clarithromycin in the management of IBD is required.This article has an associated First Person interview with the joint first authors of the paper.

Highlights

Inflammatory bowel diseases (IBD) affect 0.5-1.0% of people in the Western world and cause substantial morbidity and cost to society(Feagan et al, 2014; van Deen et al, 2014)
Motif Enrichment Analysis using Logistic Regression (MEALR) Transcription regulatory feedback loops driven by NF-kappaB/RelA and cooperating transcription factors were inferred based on existing knowledge about signalling pathways involving NF-kappaB/RelA transcription factor binding motifs and ChIP-seq experiment data targeting NF-kappaB/RelA-bound sites in the human genome
Among the target genes we identified 24 transcription factors inferred by MEALR as well as 90 of 284 genes encoding components of signalling pathways and cascades involving NFkappaB/RelA collected from the TRANSPATH(R) database, release 2013.3

Summary

Introduction

Inflammatory bowel diseases (IBD) affect 0.5-1.0% of people in the Western world and cause substantial morbidity and cost to society(Feagan et al, 2014; van Deen et al, 2014). Signalling, we developed an analysis workflow to identify genes encoding potential components of transcription regulatory feedback loops combining known NF-κB-involving signalling pathways, ChIP-seq assay based NF-κB/RelA-bound genomic regions from the ENCODE project (GEO series GSE31477), and a newly-developed method to find combinations of enriched DNA-sequence motifs (Motif Enrichment Analysis by Logistic Regression (MEALR)) (see supplementary materials for details).

Results

Conclusion