Kynurenine-3-monooxygenase inhibition prevents multiple organ failure in rodent models of acute pancreatitis. |
Authors: |
Mole, DJ Webster, SP Uings, I Zheng, X Binnie, M Wilson, K Hutchinson, JP Mirguet, O Walker, A Beaufils, B Ancellin, N Trottet, L Beneton, V Mowat, CG Wilkinson, M Rowland, P Haslam, C McBride, A Homer, NZ Baily, JE Sharp, MG Garden, OJ Hughes, J Howie, SE Holmes, DS Liddle, J Iredale, JP
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Citation: |
Mole DJ, etal., Nat Med. 2016 Feb;22(2):202-9. doi: 10.1038/nm.4020. Epub 2016 Jan 11. |
RGD ID: |
11342439 |
Pubmed: |
PMID:26752518 (View Abstract at PubMed) |
PMCID: |
PMC4871268 (View Article at PubMed Central) |
DOI: |
DOI:10.1038/nm.4020 (Journal Full-text) |
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 A 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.
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