title: 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. 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.
authors.affiliation: Medical Research Council Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK.|Clinical Surgery, University of Edinburgh, Edinburgh, UK.
authors.forename: Damian J
authors.identifier: http://orcid.org/0000-0001-6884-7302
authors.initials: DJ
authors.lastname: Mole
authors.affiliation: University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.
authors.forename: Scott P
authors.initials: SP
authors.lastname: Webster
authors.affiliation: Discovery Partnerships with Academia, GlaxoSmithKline, Stevenage, UK.
authors.forename: Iain
authors.initials: I
authors.lastname: Uings
authors.affiliation: Medical Research Council Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK.
authors.forename: Xiaozhong
authors.initials: X
authors.lastname: Zheng
authors.affiliation: University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.
authors.forename: Margaret
authors.initials: M
authors.lastname: Binnie
authors.affiliation: University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.
authors.forename: Kris
authors.initials: K
authors.lastname: Wilson
authors.affiliation: Molecular Discovery Research, GlaxoSmithKline, Stevenage, UK.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Hutchinson
authors.affiliation: Flexible Discovery Unit, GlaxoSmithKline, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Mirguet
authors.affiliation: Discovery Partnerships with Academia, GlaxoSmithKline, Stevenage, UK.
authors.forename: Ann
authors.initials: A
authors.lastname: Walker
authors.affiliation: Flexible Discovery Unit, GlaxoSmithKline, Paris, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Beaufils
authors.affiliation: Flexible Discovery Unit, GlaxoSmithKline, Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Ancellin
authors.affiliation: Flexible Discovery Unit, GlaxoSmithKline, Paris, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Trottet
authors.affiliation: Flexible Discovery Unit, GlaxoSmithKline, Paris, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Bénéton
authors.affiliation: EastChem School of Chemistry, University of Edinburgh, Edinburgh, UK.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Mowat
authors.affiliation: EastChem School of Chemistry, University of Edinburgh, Edinburgh, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Wilkinson
authors.affiliation: Molecular Discovery Research, GlaxoSmithKline, Stevenage, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Rowland
authors.affiliation: Molecular Discovery Research, GlaxoSmithKline, Stevenage, UK.
authors.forename: Carl
authors.initials: C
authors.lastname: Haslam
authors.affiliation: University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: McBride
authors.affiliation: Mass Spectrometry Core, University of Edinburgh, Edinburgh, UK.
authors.forename: Natalie Z M
authors.initials: NZ
authors.lastname: Homer
authors.affiliation: University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.
authors.forename: James E
authors.initials: JE
authors.lastname: Baily
authors.affiliation: Central Bioresearch Services, University of Edinburgh, Edinburgh, UK.
authors.forename: Matthew G F
authors.initials: MG
authors.lastname: Sharp
authors.affiliation: Clinical Surgery, University of Edinburgh, Edinburgh, UK.
authors.forename: O James
authors.initials: OJ
authors.lastname: Garden
authors.affiliation: Medical Research Council Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Hughes
authors.affiliation: Medical Research Council Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK.
authors.forename: Sarah E M
authors.initials: SE
authors.lastname: Howie
authors.affiliation: Discovery Partnerships with Academia, GlaxoSmithKline, Stevenage, UK.
authors.forename: Duncan S
authors.initials: DS
authors.lastname: Holmes
authors.affiliation: Discovery Partnerships with Academia, GlaxoSmithKline, Stevenage, UK.
authors.forename: John
authors.initials: J
authors.lastname: Liddle
authors.affiliation: Medical Research Council Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK.
authors.forename: John P
authors.initials: JP
authors.lastname: Iredale
mesh_terms: D000208:Acute Disease; D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology*; D002853:Chromatography, Liquid; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D057809:HEK293 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D050601:Kynurenine 3-Monooxygenase / Q000037:antagonists & inhibitors* / Q000235:genetics; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009102:Multiple Organ Failure / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D023303:Oxazolidinones / Q000494:pharmacology*; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010195:Pancreatitis / Q000150:complications / Q000235:genetics* / Q000473:pathology; D011422:Propionates / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D053719:Tandem Mass Spectrometry; D014364:Tryptophan / Q000378:metabolism
chemical_list: D001583:Benzoxazoles; C000608561:GSK180; D023303:Oxazolidinones; D011422:Propionates; D012333:RNA, Messenger; D014364:Tryptophan; D050601:Kynurenine 3-Monooxygenase