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

SysmedIBD consortium, Katie Lloyd, Stamatia Papoutsopoulou, Emily Smith, Philip Stegmaier, Francois Bergey, Lona Morris, Madeleine Kittner, Hazel England, Dave Spiller, Michael White, Barry J Campbell, Carria A Duckworth, Vladimir Poroikov, Vitor AP Martins dos Santos, Alexander Kel, Werner Muller, D Mark Pritchard, Chris Probert, Michael D Burkitt

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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. 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. 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. 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. 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.
Original languageEnglish
JournalDMM Disease Models and Mechanisms
Early online date21 Sept 2020
Publication statusPublished - 21 Sept 2020


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