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

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posted on 24.07.2019, 14:42 by S Zhang, M Sakuma, GS Deora, CW Levy, A Klausing, C Breda, KD Read, CD Edlin, BP Ross, M Wright Muelas, PJ Day, S O’Hagan, DB Kell, R Schwarcz, D Leys, DJ Heyes, F Giorgini, NS Scrutton
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.

Funding

The work was funded by the Biotechnology and Biological Sciences Research Council (BB/P009042/1, BB/R000093/1 and BB/M017702/1 to N.S.S.), the Engineering and Physical Sciences Research Council (fellowship to N.S.S.; EP/J020192/1), the Medical Research Council (MR/N00373X/1, F.G.), the Proof of Concept scheme from the University of Leicester (F.G., N.S.S.), Leicester Drug Discovery and Diagnostics (LD3) small grant award (F.G., N.S.S.) and NIMH grant P50 MH103222 (R.S.). We thank Gillian P. Bates (University College, London), Robert P. Mason (University of Leicester) and Ruth C. Barber (LD3) for experimental support, and acknowledge Biofocus DPI (Charles River Laboratories) and WuXi AppTec for contract research services provided. We thank Diamond Light Source for access to beamlines i03 & i04 (proposal numbers MX8997-35, MX12788-8, 19, 42 & 62) that contributed to the results presented here.

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Citation

Communications Biology, 2019, 2 (1), 271

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/Biological Sciences/Genetics and Genome Biology

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VoR (Version of Record)

Published in

Communications Biology

Publisher

Nature Research (part of Springer Nature)

issn

2399-3642

Acceptance date

28/06/2019

Copyright date

2019

Available date

24/07/2019

Publisher version

https://www.nature.com/articles/s42003-019-0520-5

Notes

The atomic coordinates and experimental data (codes 6FP0, 6FP1, 6FPH, 6FOX, 6FOY & 6FOZ) have been deposited in the Protein Data Bank (www.wwpdb.org). Raw data used for Fig. 3 are available in Supplementary Data 1. All other data are available from the corresponding author on reasonable request. Supplementary information accompanies this paper at https://doi.org/10.1038/s42003-019-0520-5.

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en

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