Corresponding Author

(2016). Kynurenine-3-monooxygenase inhibition prevents multiple organ failure in rodent models of acute pancreatitis. General rights This document is made available in accordance with publisher policies. Please cite only the published version using the reference above. Full terms of use are available: Explore Bristol Research is a digital archive and the intention is that deposited content should not be removed. However, if you believe that this version of the work breaches copyright law please contact [email protected] and include the following information in your message: • Your contact details • Bibliographic details for the item, including a URL • An outline of the nature of the complaint On receipt of your message the Open Access Team will immediately investigate your claim, make an initial judgement of the validity of the claim and, where appropriate, withdraw the item in question from public view. 1 Kynurenine–3–monooxygenase inhibition prevents multiple organ failure in rodent models of acute pancreatitis. 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 1,2 Acute mortality from AP-MODS exceeds 20% 3 and for those who survive the initial episode, their lifespan is typically shorter than the general population 4. There are no specific therapies available that protect individuals against 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 deficient for Kmo with a robust biochemical phenotype that protected against extrapancreatic tissue injury to lung, kidney and liver in experimental AP-MODS. A medicinal chemistry strategy based on modifications of the kynurenine substrate led to the discovery of 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 levels of kynurenine pathway metabolites in vivo and afforded therapeutic protection against AP-MODS in a rat model of AP. Our findings establish KMO inhibition as a novel therapeutic strategy in the treatment of AP-MODS and open up a new area for drug discovery in critical illness. Systemic tryptophan metabolism in mammals occurs primarily via the kynurenine pathway (Fig. 1a) 5. Tryptophan metabolites contribute to acute lung injury in rats with AP 6 , while the tryptophan …