A brain-permeable inhibitor of the neurodegenerative disease target kynurenine 3-monooxygenase prevents accumulation of neurotoxic metabolites.
Chemical biology
Drug discovery
Neurodegeneration
X-ray crystallography
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
2019
2019
Historique:
received:
30
07
2018
accepted:
28
06
2019
entrez:
3
8
2019
pubmed:
3
8
2019
medline:
3
8
2019
Statut:
epublish
Résumé
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 (
Identifiants
pubmed: 31372510
doi: 10.1038/s42003-019-0520-5
pii: 520
pmc: PMC6656724
doi:
Substances chimiques
Enzyme Inhibitors
0
Hydrogen Peroxide
BBX060AN9V
Kynurenine 3-Monooxygenase
EC 1.14.13.9
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Pagination
271Subventions
Organisme : NIMH NIH HHS
ID : P50 MH103222
Pays : United States
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/P009042/1
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/R000093/1
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/M017702/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/N00373X/1
Pays : United Kingdom
Déclaration de conflit d'intérêts
Competing interestsThe authors declare no competing non-financial interests but the following competing financial interests: a patent (new compounds and uses) from the University of Leicester and University of Manchester by N.S.S. and F.G. is pending, application number 1719327.7.
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