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

Communications Biology
Shaowei ZhangNigel S Scrutton

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.

References

Feb 15, 2000·European Journal of Biochemistry·J BretonA Isacchi
Feb 20, 2009·Journal of Neurochemistry·Laura AmoriRobert Schwarcz
Jun 4, 2011·Current Biology : CB·Susanna CampesanFlaviano Giorgini
Jun 9, 2012·Nature Reviews. Neuroscience·Robert SchwarczHui-Qiu Wu
Apr 12, 2013·Nature·Marta AmaralNigel S Scrutton
Mar 10, 2015·Metabolomics : Official Journal of the Metabolomic Society·Steve O HaganDouglas B Kell
Mar 17, 2015·Seminars in Cell & Developmental Biology·Daniel C Maddison, Flaviano Giorgini
Nov 22, 2015·Drug Discovery Today·Jason R SmithGilles J Guillemin
Apr 27, 2016·Proceedings of the National Academy of Sciences of the United States of America·Carlo BredaFlaviano Giorgini
Jun 7, 2016·Neuropharmacology·Jong-Min LeeGilles J Guillemin
Mar 25, 2017·Bioorganic & Medicinal Chemistry Letters·John LiddleScott P Webster
Aug 10, 2017·The New England Journal of Medicine·Hongjun ShiSally L Dunwoodie

❮ Previous
Next ❯

Citations

Nov 11, 2020·PLoS Genetics·Daniel C MaddisonFlaviano Giorgini
Feb 6, 2021·Communications Biology·Shinya MimasuKenichi Kakefuda
Jan 19, 2021·Archives of Biochemistry and Biophysics·Renata A G ReisPablo Sobrado

❮ Previous
Next ❯

Methods Mentioned

BETA
size exclusion chromatography

Software Mentioned

Phenix
MassLynx
Prism
GraphPad
Phaser
COOT

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.