DOI: 10.1101/513838Jan 7, 2019Paper

Identification of a novel therapeutic agent for Inflammatory Bowel Disease guided by systems medicine

BioRxiv : the Preprint Server for Biology
Katie Lloyd

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 dextr...Continue Reading

Related Concepts

Colitis
Pharmaceutical Preparations
Inflammatory Bowel Diseases
Intestines, Small
Intestines
Lipopolysaccharides
Macrophage
Laboratory mice
Mus
Computer Software

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