A brain-permeable inhibitor of the neurodegenerative disease target kynurenine 3-monooxygenase prevents accumulation of neurotoxic metabolites.
A brain-permeable inhibitor of the neurodegenerative disease target kynurenine 3-monooxygenase prevents accumulation of neurotoxic metabolites.
复制标题
神经退行性疾病的脑渗透性抑制剂以犬尿氨酸 3-单加氧酶为靶点，可防止神经毒性代谢物的积累。
DOI：
10.1038/s42003-019-0520-5
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发表时间：
2019
影响因子：
5.9
通讯作者：
Zhang S
中科院分区：
文献类型：
--
作者：
Zhang S
犬尿氨酸途径（KP）的失调导致与几种神经退行性疾病（包括亨廷顿病（HD））的发病机制相关的神经活性代谢物的失衡。抑制KP中的犬尿氨酸3-单加氧酶（KMO）使这些代谢失衡正常化，并改善几种神经退行性疾病模型中的神经退行性疾病和相关表型。因此，KMO是这些疾病的有希望的候选药物靶标，但已知的抑制剂不是脑渗透性的。在这里，已经鉴定了19种新的KMO抑制剂。其中之一（1）在果蝇HD模型中具有神经保护作用，但在小鼠中具有极低的脑渗透性。前药变体（1b）穿过血脑屏障，在脑中释放1，从而降低3-羟基犬尿氨酸（一种与神经变性相关的毒性KP代谢物）的水平。前药1b将促进针对多种神经退行性和神经炎症性疾病的靶向治疗的发展，其中KP可能发挥作用，包括HD，阿尔茨海默病和帕金森病。
Dysregulation of the kynurenine pathway (KP) leads to imbalances in neuroactive metabolites associated with the pathogenesis of several neurodegenerative disorders, including Huntington’s disease (HD). Inhibition of the enzyme kynurenine 3-monooxygenase (KMO) in the KP normalises these metabolic imbalances and ameliorates neurodegeneration and related phenotypes in several neurodegenerative disease models. KMO is thus a promising candidate drug target for these disorders, but known inhibitors are not brain permeable. Here, 19 new KMO inhibitors have been identified. One of these (1) is neuroprotective in aDrosophilaHD model but is minimally brain penetrant in mice. The prodrug variant (1b) crosses the blood–brain barrier, releases1in the brain, thereby lowering levels of 3-hydroxykynurenine, a toxic KP metabolite linked to neurodegeneration. Prodrug1bwill advance development of targeted therapies against multiple neurodegenerative and neuroinflammatory diseases in which KP likely plays a role, including HD, Alzheimer’s disease, and Parkinson’s disease.