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

Shaowei Zhang, Michiyo Sakuma, Girdhar S. Deora, Colin W. Levy, Alex Klausing, Carlo Breda, Kevin D. Read, Chris D. Edlin, Benjamin P. Ross, Marina Wright Muelas, Philip J. Day, Stephen O'Hagan, Douglas B. Kell, Robert Schwarcz, David Leys, Derren J. Heyes, Flaviano Giorgini (Lead / Corresponding author), Nigel S. Scrutton (Lead / Corresponding author)

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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 (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.

Original languageEnglish
Article number271
Pages (from-to)1-10
Number of pages10
JournalCommunications Biology
Volume2
Early online date24 Jul 2019
DOIs
Publication statusPublished - 24 Jul 2019

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