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

Research output: Contribution to journalArticle

Authors

  • Laura Osgerby
  • Peter J Thornton
  • Joseph Amalfitano
  • Cécile S Le Duff
  • Iqra Jabeen
  • Ageo Miccoli
  • Miratul M K Muqit
  • Youcef Mehellou

External organisations

  • University of Dundee
  • School of Pharmacy, University of Birmingham , Birmingham, B15 2TT, U.K.
  • Cardiff University
  • School of Chemistry, University of Birmingham , Birmingham, B15 2TT, U.K.

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.

Details

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