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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29 Citations (Scopus)
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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

Keywords

  • Neurodegeneration
  • Nucleoside
  • Parkinson
  • PINK1
  • ProTide

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    Muqit, Miratul

    • MRC PPU - Professor (Clinical) & Personal Chair of Experimental Neurology (Clinical)

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