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 (1) is neuroprotective in a Drosophila HD model but is minimally brain penetrant in mice. The prodrug variant (1b) crosses the blood-brain barrier, releases 1 in the brain, thereby lowering levels of 3-hydroxykynurenine, a toxic KP metabolite linked to neurodegeneration. Prodrug 1b 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: | Chemical biology, Drug discovery, Neurodegeneration, X-ray crystallography, Animals, Blood-Brain Barrier, Brain, Enzyme Inhibitors, Hydrogen Peroxide, Kynurenine 3-Monooxygenase, Mice, Neurodegenerative Diseases |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 02 Oct 2019 09:11 |
| Last Modified: | 19 Jan 2023 00:24 |
| 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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