Using systems medicine to identify a therapeutic agent with potential for repurposing in Inflammatory Bowel Disease
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Le résumé fourni par la source
Abstract 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.
Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.
Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Using systems medicine to identify a therapeutic agent with potential for repurposing in Inflammatory Bowel Disease
- Date Crossref
- 07/01/2019
- Éditeur
- openRxiv
- Type
- posted-content
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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University of Liverpool Department of Cellular and Molecular Physiology pays non établi dans la noticeUniversité ou école supérieure
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University of Manchester pays non établi dans la noticeUniversité ou école supérieure
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GeneXplain (Germany) pays non établi dans la noticeEntreprise
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LifeGlimmer (Germany) pays non établi dans la noticeEntreprise
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Institute of Biomedical Chemistry pays non établi dans la noticeStructure de recherche
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Faculty of Biology Medicine and Health pays non établi dans la noticeUniversité ou école supérieure
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geneXplain GmbH pays non établi dans la noticeEntreprise
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LifeGlimmer GmbH pays non établi dans la noticeEntreprise
Department of Cellular and Molecular Physiology — University of Liverpool, University of Manchester et GeneXplain (Germany), avec 5 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.