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. 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.
School of Chemistry, University of Birmingham , Birmingham, B15 2TT, U.K.
Laura
L
Osgerby
MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee , Dundee DD1 5EH, U.K.
Yu-Chiang
YC
Lai
School of Pharmacy, University of Birmingham , Birmingham, B15 2TT, U.K.
Peter J
PJ
Thornton
School of Chemistry, University of Birmingham , Birmingham, B15 2TT, U.K.
Joseph
J
Amalfitano
School of Chemistry, University of Birmingham , Birmingham, B15 2TT, U.K.
Cécile S
0000-0003-3585-9491
CS
Le Duff
School of Chemistry, University of Birmingham , Birmingham, B15 2TT, U.K.
Iqra
I
Jabeen
School of Pharmacy, University of Birmingham , Birmingham, B15 2TT, U.K.
Hachemi
H
Kadri
School of Pharmacy and Pharmaceutical Sciences, Cardiff University , Cardiff CF10 3NB, U.K.
Ageo
A
Miccoli
School of Chemistry, University of Birmingham , Birmingham, B15 2TT, U.K.
James H R
JHR
Tucker
MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee , Dundee DD1 5EH, U.K.|School of Medicine, University of Dundee , Dundee, DD1 9SY, U.K.
Miratul M K
MMK
Muqit
School of Pharmacy and Pharmaceutical Sciences, Cardiff University , Cardiff CF10 3NB, U.K.
Youcef
0000-0001-5720-8513
Y
Mehellou
D000241:Adenosine / Q000494:pharmacology*; D000818:Animals; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D006801:Humans; D007701:Kinetin / Q000494:pharmacology*; D008928:Mitochondria / Q000201:enzymology*; D010300:Parkinson Disease / Q000201:enzymology*; D011494:Protein Kinases / Q000378:metabolism*; D066244:Proton Magnetic Resonance Spectroscopy; D021241:Spectrometry, Mass, Electrospray Ionization; D000099202:PTEN-Induced Putative Kinase
D000241:Adenosine; D007701:Kinetin; D011494:Protein Kinases; D000099202:PTEN-Induced Putative Kinase; C527965:kinetin riboside