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

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....

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Published inJournal of medicinal chemistry Vol. 60; no. 8; pp. 3518 - 3524
Main Authors 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
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 27.04.2017
Amer Chemical Soc
Subjects
Adenosine - pharmacology
Animals
Brief
Carbon-13 Magnetic Resonance Spectroscopy
Chemistry, Medicinal
Humans
Kinetin - pharmacology
Life Sciences & Biomedicine
Mitochondria - enzymology
Parkinson Disease - enzymology
Pharmacology & Pharmacy
Protein Kinases - metabolism
Proton Magnetic Resonance Spectroscopy
Science & Technology
Spectrometry, Mass, Electrospray Ionization
CELLS
PHOSPHORYLATION
SUBSTRATE
PRODRUGS
MUTATIONS
TECHNOLOGY
BINDING
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Summary: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.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.6b01897