Journal
NATURE MEDICINE
Volume 22, Issue 2, Pages 202-209Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.4020
Keywords
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Funding
- Clinician Scientist Fellowship from the Health Foundation/Academy of Medical Sciences
- Medical Research Council Developmental Pathway Funding Stream
- Wellcome Trust Institutional Strategic Support Fund
- Medical Research Council
- Medical Research Council Centre for Inflammation Research
- Medical Research Council [G0901697, G0600033, MR/J010766/1, MC_G0900869] Funding Source: researchfish
- MRC [G0600033, G0901697, MC_G0900869, MR/J010766/1] Funding Source: UKRI
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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(1,2). 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(4). 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(5), 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 AR 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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