1区 · 医学
Article
作者: Mole, Damian J ; Zheng, Xiaozhong ; McBride, Andrew ; Rowland, Paul ; Mowat, Christopher G ; Liddle, John ; Binnie, Margaret ; Holmes, Duncan S ; Iredale, John P ; Haslam, Carl ; Wilkinson, Martin ; Wilson, Kris ; Baily, James E ; Beaufils, Benjamin ; Webster, Scott P ; Ancellin, Nicolas ; Uings, Iain ; Howie, Sarah E M ; Bénéton, Véronique ; Mirguet, Olivier ; Hutchinson, Jonathan P ; Hughes, Jeremy ; Trottet, Lionel ; Garden, O James ; Homer, Natalie Z M ; Walker, Ann ; Sharp, Matthew G F
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.
