Inflammatory bowel disease (IBD) is a chronic and incurable disease characterised by episodic and disabling inflammation of the gut. Current therapeutic strategies aim to decrease the frequency and severity of inflammatory episodes to prevent progression of bowel damage and avoid disabling disease with need for surgery. However, these therapeutic options suffer from poor compliance, toxicity or cost.
There is an urgent need for better therapeutics. With clear evidence that intestinal immunity is regulated through microbiome-immune crosstalk, the microbiome has now emerged as a valuable potential source for immune-modifying IBD therapeutics.
Researchers at The University of Queensland (UQ) have isolated gut bacteria that secreted soluble suppressors of the pro-inflammatory NF-κβ pathway, and identified a novel class of NF-κβ inhibitory bioactives. Based on the bioactives, a lead compound with potent NF-κβ activity (IC50 = 1 nM) was synthesised.
Preliminary pharmacokinetic profiling in mice shows that the lead compound is detectable at active concentrations throughout the ileum and colon less than 1 hour following oral administration and remains at concentrations >100×IC50 for >6 hours.
Key features
- Leverage benefits of microbiome to treat IBD
- Novel molecules potently inhibit NF-κβ pathway throughout the colon
- Comparable reduction in disease severity to biologic therapies
- Orally active, with >6 hours gut stability and favourable PK profile.