Kynurenine-3-monooxygenase inhibition prevents multiple organ failure in rodent models of acute pancreatitis

Damian J Mole, Scott P Webster, Iain Uings, Xiaozhong Zheng, Margaret Binnie, Kris Wilson, Jonathan P Hutchinson, Olivier Mirguet, Ann Walker, Benjamin Beaufils, Nicolas Ancellin, Lionel Trottet, Véronique Bénéton, Christopher G Mowat, Martin Wilkinson, Paul Rowland, Carl Haslam, Andrew McBride, Natalie Z M Homer, James E BailyMatthew G F Sharp, O James Garden, Jeremy Hughes, Sarah E M Howie, Duncan S Holmes, John Liddle, John P Iredale

Research output: Contribution to journalArticle (Academic Journal)peer-review

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Abstract

Acute pancreatitis (AP) is a common and devastating inflammatory condition of the pancreas that is considered to be a paradigm of sterile inflammation leading to systemic multiple organ dysfunction syndrome (MODS) and death. Acute mortality from AP-MODS exceeds 20% (ref. 3), and the lifespans of those who survive the initial episode are typically shorter than those of the general population. There are no specific therapies available to protect individuals from AP-MODS. Here we show that kynurenine-3-monooxygenase (KMO), a key enzyme of tryptophan metabolism, is central to the pathogenesis of AP-MODS. We created a mouse strain that is deficient for Kmo (encoding KMO) and that has a robust biochemical phenotype that protects against extrapancreatic tissue injury to the lung, kidney and liver in experimental AP-MODS. A medicinal chemistry strategy based on modifications of the kynurenine substrate led to the discovery of the oxazolidinone GSK180 as a potent and specific inhibitor of KMO. The binding mode of the inhibitor in the active site was confirmed by X-ray co-crystallography at 3.2 Å resolution. Treatment with GSK180 resulted in rapid changes in the levels of kynurenine pathway metabolites in vivo, and it afforded therapeutic protection against MODS in a rat model of AP. Our findings establish KMO inhibition as a novel therapeutic strategy in the treatment of AP-MODS, and they open up a new area for drug discovery in critical illness.

Original languageEnglish
Pages (from-to)202-209
Number of pages8
JournalNature Medicine
Volume22
Issue number2
Early online date11 Jan 2016
DOIs
Publication statusPublished - Feb 2016

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