Advantages of brain penetrating inhibitors of kynurenine-3-monooxygenase for treatment of neurodegenerative diseases

Shaowei Zhang, Mary E W Collier, Derren Heyes, Flaviano Giorgini, Nigel Scrutton

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Abstract

Kynurenine-3-monooxygenase (KMO) is an important therapeutic target for several brain disorders that has been extensively studied in recent years. Potent inhibitors towards KMO have been developed and tested within different disease models, showing great therapeutic potential, especially in models of neurodegenerative disease. The inhibition of KMO reduces the production of downstream toxic kynurenine pathway metabolites and shifts the flux to the formation of the neuroprotectant kynurenic acid. However, the efficacy of KMO inhibitors in neurodegenerative disease has been limited by their poor brain permeability. Combined with virtual screening and prodrug strategies, a novel brain penetrating KMO inhibitor has been developed which dramatically decreases neurotoxic metabolites. This review highlights the importance of KMO as a drug target in neurological disease and the benefits of brain permeable inhibitors in modulating kynurenine pathway metabolites in the central nervous system.
Original languageEnglish
JournalArchives of Biochemistry and Biophysics
Early online date1 Dec 2020
DOIs
Publication statusE-pub ahead of print - 1 Dec 2020

Research Beacons, Institutes and Platforms

  • Manchester Institute of Biotechnology

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  • Biochemical and Biophysical Sciences Technology Platform

    Heyes, D. (Senior Technical Specialist), Boothman, C. (Senior Technical Specialist), Cliffe, L. (Technical Specialist), Dunstan, M. (Senior Technical Specialist), Golovanova, M. (Senior Technician), Hoeven, R. (Technical Specialist), Lopez Perez, R. (Senior Technician), Sakuma, M. (Senior Technician), Tait, S. (Senior Technician) & Tilakaratna, V. (Senior Technician)

    FSE Research

    Facility/equipment: Platform

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