Kinetin Riboside and Its ProTides Activate the Parkinson’s Disease Associated PTEN-Induced Putative Kinase 1 (PINK1) Independent of Mitochondrial Depolarization

Laura Osgerby; Yu-Chiang Lai; Peter J. Thornton; Joseph Amalfitano; Cécile S. Le Duff; Iqra Jabeen; Hachemi Kadri; Ageo Miccoli; James H. R. Tucker; Miratul M. K. Muqit; Youcef Mehellou

doi:10.1021/acs.jmedchem.6b01897

Kinetin Riboside and Its ProTides Activate the Parkinson’s Disease Associated PTEN-Induced Putative Kinase 1 (PINK1) Independent of Mitochondrial Depolarization

Laura Osgerby, Yu-Chiang Lai, Peter J. Thornton, Joseph Amalfitano, Cécile S. Le Duff, Iqra Jabeen, Hachemi Kadri, Ageo Miccoli, James H. R. Tucker, Miratul M. K. Muqit (Lead / Corresponding author), Youcef Mehellou (Lead / Corresponding author)

MRC PPU

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Abstract

Since loss of function mutations of PINK1 lead to early-onset Parkinson’s disease, there has been growing interest in the discovery of small molecules that amplify the kinase activity of PINK1. We herein report the design, synthesis, serum stability and hydrolysis of four kinetin riboside ProTides. These ProTides, along with kinetin riboside, activated PINK1 in cells independent of mitochondrial depolarization. This highlights the potential of modified nucleosides and their phosphate prodrugs as treatments for neurodegenerative diseases.

Original language	English
Pages (from-to)	3518-3524
Number of pages	7
Journal	Journal of Medicinal Chemistry
Volume	60
Issue number	8
Early online date	21 Mar 2017
DOIs	https://doi.org/10.1021/acs.jmedchem.6b01897
Publication status	Published - 27 Apr 2017

Keywords

Neurodegeneration
Nucleoside
Parkinson
PINK1
ProTide

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Final published version, 1.92 MBLicence: CC BY

Muqit, Miratul
- MRC PPU - Professor (Clinical) of Experimental Neurology (Clinical)
Person: Academic

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Osgerby, L., Lai, Y.-C., Thornton, P. J., Amalfitano, J., Le Duff, C. S., Jabeen, I., Kadri, H., Miccoli, A., Tucker, J. H. R., Muqit, M. M. K., & Mehellou, Y. (2017). Kinetin Riboside and Its ProTides Activate the Parkinson’s Disease Associated PTEN-Induced Putative Kinase 1 (PINK1) Independent of Mitochondrial Depolarization. Journal of Medicinal Chemistry, 60(8), 3518-3524. https://doi.org/10.1021/acs.jmedchem.6b01897

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title = "Kinetin Riboside and Its ProTides Activate the Parkinson{\textquoteright}s Disease Associated PTEN-Induced Putative Kinase 1 (PINK1) Independent of Mitochondrial Depolarization",

abstract = "Since loss of function mutations of PINK1 lead to early-onset Parkinson{\textquoteright}s disease, there has been growing interest in the discovery of small molecules that amplify the kinase activity of PINK1. We herein report the design, synthesis, serum stability and hydrolysis of four kinetin riboside ProTides. These ProTides, along with kinetin riboside, activated PINK1 in cells independent of mitochondrial depolarization. This highlights the potential of modified nucleosides and their phosphate prodrugs as treatments for neurodegenerative diseases.",

keywords = "Neurodegeneration, Nucleoside, Parkinson, PINK1, ProTide",

author = "Laura Osgerby and Yu-Chiang Lai and Thornton, {Peter J.} and Joseph Amalfitano and {Le Duff}, {C{\'e}cile S.} and Iqra Jabeen and Hachemi Kadri and Ageo Miccoli and Tucker, {James H. R.} and Muqit, {Miratul M. K.} and Youcef Mehellou",

note = "M.M.K.M. is funded by a Wellcome Trust Senior Research Fellowship in Clinical Science (101022/Z/13/Z), the Medical Research Council; Parkinson{\textquoteright}s UK; the Michael J. Fox Foundation; J. Macdonald Menzies Charitable Trust Prize Studentship, Biotechnology and Biological Sciences Research Council; and the EMBO Young Investigator Programme.",

year = "2017",

month = apr,

day = "27",

doi = "10.1021/acs.jmedchem.6b01897",

language = "English",

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pages = "3518--3524",

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Osgerby, L, Lai, Y-C, Thornton, PJ, Amalfitano, J, Le Duff, CS, Jabeen, I, Kadri, H, Miccoli, A, Tucker, JHR, Muqit, MMK & Mehellou, Y 2017, 'Kinetin Riboside and Its ProTides Activate the Parkinson’s Disease Associated PTEN-Induced Putative Kinase 1 (PINK1) Independent of Mitochondrial Depolarization', Journal of Medicinal Chemistry, vol. 60, no. 8, pp. 3518-3524. https://doi.org/10.1021/acs.jmedchem.6b01897

TY - JOUR

T1 - Kinetin Riboside and Its ProTides Activate the Parkinson’s Disease Associated PTEN-Induced Putative Kinase 1 (PINK1) Independent of Mitochondrial Depolarization

AU - Osgerby, Laura

AU - Lai, Yu-Chiang

AU - Thornton, Peter J.

AU - Amalfitano, Joseph

AU - Le Duff, Cécile S.

AU - Jabeen, Iqra

AU - Kadri, Hachemi

AU - Miccoli, Ageo

AU - Tucker, James H. R.

AU - Muqit, Miratul M. K.

AU - Mehellou, Youcef

N1 - M.M.K.M. is funded by a Wellcome Trust Senior Research Fellowship in Clinical Science (101022/Z/13/Z), the Medical Research Council; Parkinson’s UK; the Michael J. Fox Foundation; J. Macdonald Menzies Charitable Trust Prize Studentship, Biotechnology and Biological Sciences Research Council; and the EMBO Young Investigator Programme.

PY - 2017/4/27

Y1 - 2017/4/27

N2 - Since loss of function mutations of PINK1 lead to early-onset Parkinson’s disease, there has been growing interest in the discovery of small molecules that amplify the kinase activity of PINK1. We herein report the design, synthesis, serum stability and hydrolysis of four kinetin riboside ProTides. These ProTides, along with kinetin riboside, activated PINK1 in cells independent of mitochondrial depolarization. This highlights the potential of modified nucleosides and their phosphate prodrugs as treatments for neurodegenerative diseases.

AB - Since loss of function mutations of PINK1 lead to early-onset Parkinson’s disease, there has been growing interest in the discovery of small molecules that amplify the kinase activity of PINK1. We herein report the design, synthesis, serum stability and hydrolysis of four kinetin riboside ProTides. These ProTides, along with kinetin riboside, activated PINK1 in cells independent of mitochondrial depolarization. This highlights the potential of modified nucleosides and their phosphate prodrugs as treatments for neurodegenerative diseases.

KW - Neurodegeneration

KW - Nucleoside

KW - Parkinson

KW - PINK1

KW - ProTide

U2 - 10.1021/acs.jmedchem.6b01897

DO - 10.1021/acs.jmedchem.6b01897

M3 - Article

C2 - 28323427

SN - 0022-2623

VL - 60

SP - 3518

EP - 3524

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 8

ER -

Kinetin Riboside and Its ProTides Activate the Parkinson’s Disease Associated PTEN-Induced Putative Kinase 1 (PINK1) Independent of Mitochondrial Depolarization

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