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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A brain-permeable inhibitor of the neurodegenerative disease target kynurenine 3-monooxygenase prevents accumulation of neurotoxic metabolites.pdf - Published version Download (1MB) | Preview |
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 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3056666 |
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