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)

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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 languageEnglish
Pages (from-to)3518-3524
Number of pages7
JournalJournal of Medicinal Chemistry
Volume60
Issue number8
Early online date21 Mar 2017
DOIs
Publication statusPublished - 27 Apr 2017

Fingerprint

Parkinson Disease
Prodrugs
Nucleosides
Neurodegenerative Diseases
Hydrolysis
Phosphotransferases
Phosphates
Mutation
Serum
kinetin riboside
PTEN-induced putative kinase

Keywords

  • Neurodegeneration
  • Nucleoside
  • Parkinson
  • PINK1
  • ProTide

Cite this

Osgerby, Laura ; Lai, Yu-Chiang ; Thornton, Peter J. ; Amalfitano, Joseph ; Le Duff, Cécile S. ; Jabeen, Iqra ; Kadri, Hachemi ; Miccoli, Ageo ; Tucker, James H. R. ; Muqit, Miratul M. K. ; Mehellou, Youcef. / Kinetin Riboside and Its ProTides Activate the Parkinson’s Disease Associated PTEN-Induced Putative Kinase 1 (PINK1) Independent of Mitochondrial Depolarization. In: Journal of Medicinal Chemistry. 2017 ; Vol. 60, No. 8. pp. 3518-3524.
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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.",
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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’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.",
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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

Kinetin Riboside and Its ProTides Activate the Parkinson’s Disease Associated PTEN-Induced Putative Kinase 1 (PINK1) Independent of Mitochondrial Depolarization. / Osgerby, Laura; Lai, Yu-Chiang; Thornton, Peter J.; Amalfitano, Joseph; Le Duff, Cécile S.; Jabeen, Iqra; Kadri, Hachemi; Miccoli, Ageo; Tucker, James H. R.; Muqit, Miratul M. K. (Lead / Corresponding author); Mehellou, Youcef (Lead / Corresponding author).

In: Journal of Medicinal Chemistry, Vol. 60, No. 8, 27.04.2017, p. 3518-3524.

Research output: Contribution to journalArticle

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

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DO - 10.1021/acs.jmedchem.6b01897

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JO - Journal of Medicinal Chemistry

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SN - 0022-2623

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