A brain-permeable inhibitor of the neurodegenerative disease target kynurenine 3-monooxygenase prevents accumulation of neurotoxic metabolites



Zhang, Shaowei, Sakuma, Michiyo, Deora, Girdhar S, Levy, Colin W, Klausing, Alex, Breda, Carlo, Read, Kevin D, Edlin, Chris D, Ross, Benjamin P, Muelas, Marina Wright
et al (show 8 more authors) (2019) A brain-permeable inhibitor of the neurodegenerative disease target kynurenine 3-monooxygenase prevents accumulation of neurotoxic metabolites. COMMUNICATIONS BIOLOGY, 2 (1). 271-.

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Abstract

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 (<b>1</b>) is neuroprotective in a <i>Drosophila</i> HD model but is minimally brain penetrant in mice. The prodrug variant (<b>1b</b>) crosses the blood-brain barrier, releases <b>1</b> in the brain, thereby lowering levels of 3-hydroxykynurenine, a toxic KP metabolite linked to neurodegeneration. Prodrug <b>1b</b> will 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.

Item Type: Article
Uncontrolled Keywords: Blood-Brain Barrier, Brain, Animals, Mice, Neurodegenerative Diseases, Hydrogen Peroxide, Enzyme Inhibitors, Kynurenine 3-Monooxygenase
Depositing User: Symplectic Admin
Date Deposited: 02 Oct 2019 09:11
Last Modified: 18 Mar 2024 04:09
DOI: 10.1038/s42003-019-0520-5
Open Access URL: https://doi.org/10.1038/s42003-019-0520-5
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URI: https://livrepository.liverpool.ac.uk/id/eprint/3056666