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

Shaowei Zhang; Michiyo Sakuma; Girdhar S. Deora; Colin Levy; Alex Klausing; Carlo Breda; Kevin D. Read; Benjamin P. Ross; Marina Wright Muelas; Philip Day; Stephen O'Hagan; Douglas Kell; Robert Schwarcz; David Leys; Derren Heyes; Flaviano Giorgini; Nigel Scrutton

doi:10.1038/s42003-019-0520-5

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

Shaowei Zhang, Michiyo Sakuma, Girdhar S. Deora, Colin Levy, Alex Klausing, Carlo Breda, Kevin D. Read, Benjamin P. Ross, Marina Wright Muelas, Philip Day, Stephen O'Hagan, Douglas Kell, Robert Schwarcz, David Leys, Derren Heyes, Flaviano Giorgini, Nigel Scrutton

Division of Evolution & Genomic Sciences (L5)

Research output: Contribution to journal › Article › peer-review

Abstract

Kynurenine 3-monooxygenase (KMO) is a candidate drug target for Huntington’s disease (HD) and other neurodegenerative disorders, but known inhibitors are not brain permeable. Here, nineteen 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. Release of 1 in the brain lowers 3-hydroxykynurenine (3-HK) levels, a toxic metabolite linked to neurodegeneration. Prodrug 1b will advance development of targeted therapies against multiple neurodegenerative and neuroinflammatory diseases in which the KP 1 likely plays a role, including HD, Alzheimer’s disease, and Parkinson’s disease.

Original language	English
Journal	Communications Biology
Early online date	24 Jul 2019
DOIs	https://doi.org/10.1038/s42003-019-0520-5
Publication status	Published - 2019

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Manchester Institute of Biotechnology

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Manchester Synthetic Biology Research Centre for Fine and Speciality Chemicals
Scrutton, N., Azapagic, A., Balmer, A., Barran, P., Breitling, R., Delneri, D., Dixon, N., Faulon, J., Flitsch, S., Goble, C., Goodacre, R., Hay, S., Kell, D., Leys, D., Lloyd, J., Lockyer, N., Martin, P., Micklefield, J., Munro, A., Pedrosa Mendes, P., Randles, S., Salehi Yazdi, F., Shapira, P., Takano, E., Turner, N. & Winterburn, J.
14/11/14 → 13/05/20
Project: Research

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Zhang, S., Sakuma, M., Deora, G. S., Levy, C., Klausing, A., Breda, C., Read, K. D., Ross, B. P., Wright Muelas, M., Day, P., O'Hagan, S., Kell, D., Schwarcz, R., Leys, D., Heyes, D., Giorgini, F., & Scrutton, N. (2019). A brain-permeable inhibitor of the neurodegenerative disease target kynurenine 3-monooxygenase prevents accumulation of neurotoxic metabolites. Communications Biology. https://doi.org/10.1038/s42003-019-0520-5

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

abstract = "Kynurenine 3-monooxygenase (KMO) is a candidate drug target for Huntington{\textquoteright}s disease (HD) and other neurodegenerative disorders, but known inhibitors are not brain permeable. Here, nineteen 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. Release of 1 in the brain lowers 3-hydroxykynurenine (3-HK) levels, a toxic metabolite linked to neurodegeneration. Prodrug 1b will advance development of targeted therapies against multiple neurodegenerative and neuroinflammatory diseases in which the KP 1 likely plays a role, including HD, Alzheimer{\textquoteright}s disease, and Parkinson{\textquoteright}s disease.",

author = "Shaowei Zhang and Michiyo Sakuma and Deora, {Girdhar S.} and Colin Levy and Alex Klausing and Carlo Breda and Read, {Kevin D.} and Ross, {Benjamin P.} and {Wright Muelas}, Marina and Philip Day and Stephen O'Hagan and Douglas Kell and Robert Schwarcz and David Leys and Derren Heyes and Flaviano Giorgini and Nigel Scrutton",

year = "2019",

doi = "10.1038/s42003-019-0520-5",

language = "English",

journal = "Communications Biology",

issn = "2399-3642",

publisher = "Springer Nature",

}

Zhang, S, Sakuma, M, Deora, GS, Levy, C, Klausing, A, Breda, C, Read, KD, Ross, BP, Wright Muelas, M, Day, P, O'Hagan, S, Kell, D, Schwarcz, R, Leys, D , Heyes, D, Giorgini, F & Scrutton, N 2019, 'A brain-permeable inhibitor of the neurodegenerative disease target kynurenine 3-monooxygenase prevents accumulation of neurotoxic metabolites', Communications Biology. https://doi.org/10.1038/s42003-019-0520-5

TY - JOUR

T1 - A brain-permeable inhibitor of the neurodegenerative disease target kynurenine 3-monooxygenase prevents accumulation of neurotoxic metabolites

AU - Zhang, Shaowei

AU - Sakuma, Michiyo

AU - Deora, Girdhar S.

AU - Levy, Colin

AU - Klausing, Alex

AU - Breda, Carlo

AU - Read, Kevin D.

AU - Ross, Benjamin P.

AU - Wright Muelas, Marina

AU - Day, Philip

AU - O'Hagan, Stephen

AU - Kell, Douglas

AU - Schwarcz, Robert

AU - Leys, David

AU - Heyes, Derren

AU - Giorgini, Flaviano

AU - Scrutton, Nigel

PY - 2019

Y1 - 2019

N2 - Kynurenine 3-monooxygenase (KMO) is a candidate drug target for Huntington’s disease (HD) and other neurodegenerative disorders, but known inhibitors are not brain permeable. Here, nineteen 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. Release of 1 in the brain lowers 3-hydroxykynurenine (3-HK) levels, a toxic metabolite linked to neurodegeneration. Prodrug 1b will advance development of targeted therapies against multiple neurodegenerative and neuroinflammatory diseases in which the KP 1 likely plays a role, including HD, Alzheimer’s disease, and Parkinson’s disease.

AB - Kynurenine 3-monooxygenase (KMO) is a candidate drug target for Huntington’s disease (HD) and other neurodegenerative disorders, but known inhibitors are not brain permeable. Here, nineteen 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. Release of 1 in the brain lowers 3-hydroxykynurenine (3-HK) levels, a toxic metabolite linked to neurodegeneration. Prodrug 1b will advance development of targeted therapies against multiple neurodegenerative and neuroinflammatory diseases in which the KP 1 likely plays a role, including HD, Alzheimer’s disease, and Parkinson’s disease.

U2 - 10.1038/s42003-019-0520-5

DO - 10.1038/s42003-019-0520-5

M3 - Article

JO - Communications Biology

JF - Communications Biology

SN - 2399-3642

ER -

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

Abstract

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