Kynurenine-3-monooxygenase inhibition prevents multiple organ failure in rodent models of acute pancreatitis.
Kynurenine-3-monooxygenase inhibition prevents multiple organ failure in rodent models of acute pancreatitis.
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DOI：
10.1038/nm.4020
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发表时间：
2016-02
期刊：
影响因子：
82.9
通讯作者：
Iredale JP
中科院分区：
文献类型：
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作者：
Mole DJ;Webster SP;Uings I;Zheng X;Binnie M;Wilson K;Hutchinson JP;Mirguet O;Walker A;Beaufils B;Ancellin N;Trottet L;Bénéton 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
急性胰腺炎（AP）是胰腺的常见和破坏性炎症状况，其被认为是导致全身性多器官功能障碍综合征（MODS）和死亡的无菌炎症的范例。AP-MODS的急性死亡率超过20%，并且对于那些在初始发作中存活的人，他们的寿命通常比一般人群短。目前还没有特定的治疗方法可以保护个体免受AP-MODS的影响。在这里，我们表明，犬尿氨酸-3-单加氧酶（KMO），色氨酸代谢的关键酶，是中央的发病机制，AP-MODS。我们创建了一个Kmo缺陷的小鼠品系，其具有强大的生化表型，可在实验性AP-MODS中保护肺、肾和肝免受胰腺外组织损伤。基于犬尿氨酸底物修饰的药物化学策略导致发现GSK 180作为KMO的有效和特异性抑制剂。通过X射线共晶体学在3.2 nm分辨率下证实了抑制剂在活性位点的结合模式。用GSK 180治疗导致体内犬尿氨酸途径代谢物水平的快速变化，并在AP大鼠模型中提供针对AP-MODS的治疗性保护。我们的研究结果确立了KMO抑制作为治疗AP-MODS的一种新的治疗策略，并为危重疾病的药物发现开辟了一个新的领域。
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% and for those who survive the initial episode, their lifespan is typically shorter than the general population. 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, 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.