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

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Lloyd, Katie, Papoutsopoulou, Stamatia ORCID: 0000-0001-6665-8508, Smith, Emily, Stegmaier, Philip, Bergey, Francois, Morris, Lorna, Kittner, Madeleine, England, Hazel, Spiller, Dave, White, Mike HR et al (show 9 more authors) , Duckworth, Carrie A ORCID: 0000-0001-9992-7540, Campbell, Barry J ORCID: 0000-0002-7407-012X, Poroikov, Vladimir, dos Santos, Vitor AP Martins, Kel, Alexander, Muller, Werner, Pritchard, D Mark ORCID: 0000-0001-7971-3561, Probert, Chris ORCID: 0000-0003-0477-6714 and Burkitt, Michael D ORCID: 0000-0002-5055-6408 (2020) Using systems medicine to identify a therapeutic agent with potential for repurposing in inflammatory bowel disease. DISEASE MODELS & MECHANISMS, 13 (11). dmm044040-.

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Abstract

Inflammatory 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 <i>in silico</i> 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 <i>in silico</i> 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.

Item Type:	Article
Uncontrolled Keywords:	Inflammatory bowel diseases, NF-kappa B, Drug repositioning, Interdisciplinary research, Organoids, Macrolide, Ulcerative colitis, Crohn's disease
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Infection, Veterinary and Ecological Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User:	Symplectic Admin
Date Deposited:	08 Nov 2021 14:26
Last Modified:	05 Oct 2023 18:06
DOI:	10.1242/dmm.044040
Open Access URL:	https://doi.org/10.1242/dmm.044040
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3141863

Available Versions of this Item

• Using systems medicine to identify a therapeutic agent with potential for repurposing in inflammatory bowel disease. (deposited 28 Sep 2020 08:08)
  • Using systems medicine to identify a therapeutic agent with potential for repurposing in inflammatory bowel disease. (deposited 08 Nov 2021 14:26) [Currently Displayed]