Lloyd, Katie 
ORCID: 0000-0002-2325-8050, Papoutsopoulou, Stamatia, Smith, Emily, Stegmaier, Philip ORCID: 0000-0002-1881-8746, Bergey, Francois, Morris, Lorna, Kittner, Madeleine, England, Hazel ORCID: 0000-0002-8324-614X, Spiller, Dave ORCID: 0000-0003-2502-6787, White, Mike HR ORCID: 0000-0002-3617-3232 et al (show 10 more authors)
(2020)
Using systems medicine to identify a therapeutic agent with potential for repurposing in inflammatory bowel disease.
Disease models & mechanisms.
|
Text
Lloyd DMM.pdf - Author Accepted Manuscript Download (3MB) | Preview |
Abstract
<h4>Objective</h4>Inflammatory bowel diseases 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 which alter NF-κB signalling and may be repositioned for use in inflammatory bowel disease.<h4>Design</h4>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-kappaB signalling, and a murine model of IBD.<h4>Results</h4>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. Clarithromycin's 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 LPS, 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.<h4>Conclusions</h4>These findings demonstrate that in-silico drug repositioning algorithms can viably be allied to laboratory validation assays in the context of inflammatory bowel disease; and that further clinical assessment of clarithromycin in the management of inflammatory bowel disease is required.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | SysmedIBD consortium |
| 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: | 26 Oct 2021 13:22 |
| Last Modified: | 18 Jan 2023 21:25 |
| DOI: | 10.1242/dmm.044040 |
| Open Access URL: | https://journals.biologists.com/dmm/article/13/11/... |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3141711 |
Dimensions
Dimensions
