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

DOI: 10.1038/s42003-019-0520-5 DOI Help

Authors: Shaowei Zhang (The University of Manchester) , Michiyo Sakuma (The University of Manchester) , Girdhar S. Deora (The University of Queensland) , Colin Levy (The University of Manchester) , Alex Klausing (University of Maryland School of Medicine) , Carlo Breda (University of Leicester) , Kevin D. Read (University of Dundee) , Chris D. Edlin (Teva Pharmaceuticals) , Benjamin P. Ross (The University of Queensland) , Marina Wright Muelas (The University of Manchester) , Philip J. Day (The University of Manchester) , Stephen O’hagan (The University of Manchester) , Douglas B. Kell (The University of Manchester) , Robert Schwarcz (University of Maryland School of Medicine) , David Leys (The University of Manchester) , Derren J. Heyes (The University of Manchester) , Flaviano Giorgini (University of Leicester) , Nigel S. Scrutton (The University of Manchester)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Communications Biology , VOL 2

State: Published (Approved)
Published: July 2019
Diamond Proposal Number(s): 8997 , 12788

Open Access Open Access

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.

Journal Keywords: Chemical biology; Drug discovery; Neurodegeneration; X-ray crystallography

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Added On: 29/07/2019 13:53


Discipline Tags:

Neurodegenerative Diseases Non-Communicable Diseases Health & Wellbeing Biochemistry Neurology Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)