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Lloyd, Katie; Papoutsopoulou, Stamatia; Smith, Emily; Stegmaier, Philip; Bergey, Francois; Morris, Lorna; Kittner, Madeleine; England, Hazel; Spiller, Dave; White, Mike H. R.; Duckworth, Carrie A.; Campbell, Barry J.; Poroikov, Vladimir; Martins dos Santos, Vitor A. P.; Kel, Alexander; Muller, Werner; Pritchard, D. Mark; Probert, Chris; Burkitt, Michael D.

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

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  • Media type: E-Article
  • Title: Using systems medicine to identify a therapeutic agent with potential for repurposing in inflammatory bowel disease
  • Contributor: Lloyd, Katie; Papoutsopoulou, Stamatia; Smith, Emily; Stegmaier, Philip; Bergey, Francois; Morris, Lorna; Kittner, Madeleine; England, Hazel; Spiller, Dave; White, Mike H. R.; Duckworth, Carrie A.; Campbell, Barry J.; Poroikov, Vladimir; Martins dos Santos, Vitor A. P.; Kel, Alexander; Muller, Werner; Pritchard, D. Mark; Probert, Chris; Burkitt, Michael D.
  • imprint: The Company of Biologists, 2020
  • Published in: Disease Models & Mechanisms
  • Language: English
  • DOI: 10.1242/dmm.044040
  • ISSN: 1754-8411; 1754-8403
  • Keywords: General Biochemistry, Genetics and Molecular Biology ; Immunology and Microbiology (miscellaneous) ; Medicine (miscellaneous) ; Neuroscience (miscellaneous)
  • Origination:
  • Footnote:
  • Description: <jats:p>Objective: 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.</jats:p> <jats:p>Design: 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.</jats:p> <jats:p>Results: 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.</jats:p> <jats:p>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.</jats:p> <jats:p>Conclusions: 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.</jats:p>
  • Access State: Open Access