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

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.

Chemical Strategies for Activating PINK1, a Protein Kinase Mutated in Parkinson's Disease

“…This was judged by parkin Ser65 phosphorylation after treatment with different concentrations of KMP ProTides. Interestingly, the nucleoside kinetin riboside was also able to activate PINK1 in cells to a level comparable to that observed with the most potent KMP ProTide . This suggested that the glycosylation of kinetin into kinetin riboside, rather than the first phosphorylation step, might be the rate‐limiting step of the four bioconversion steps from kinetin to the active KTP.…”

“…Encouraged by the success of the ProTide technology in discovering nucleotide‐based therapeutics, we applied this prodrug approach to kinetin riboside monophosphate, KMP . Four KMP ProTides were synthesised with various esters (methyl, isopropyl, tert ‐butyl and benzyl).…”

“…They were shown to be stable in human serum for >12 h and were metabolised in vitro by carboxypeptidase Y to generate the desired nucleotide metabolite. When studied for their ability to activate PINK1 in HEK293 cells stably overexpressing PINK1 and transiently transfected with parkin, these ProTide prodrugs showed far superior activation of PINK1 compared to the parent nucleobase kinetin . This was judged by parkin Ser65 phosphorylation after treatment with different concentrations of KMP ProTides.…”

“…[19] Encouraged by the success of the ProTide technologyi nd iscoveringn ucleotide-based therapeutics, we appliedt his prodrug approacht ok inetin riboside monophosphate, KMP. [21] Four KMP ProTides were synthesised with variouse sters (methyl, isopropyl, tert-butyla nd benzyl). They were shown to be stable in human serum for > 12 ha nd were metabolised in vitro by carboxypeptidase Yt og enerate the desired nucleotide metabolite.…”

Expedient synthesis and biological evaluation of alkenyl acyclic nucleoside phosphonate prodrugs

“…2,10,11 Given the tremendous importance of phosphor(n)oamidate prodrugs in the antiviral arena and beyond, after the approval of Sofosbuvir and TAF, the application of the ProTide technology has grown dramatically and it has started to show very promising results in other therapeutic areas as well. [12][13][14] While there are several efficient procedures to synthesize phosphoroamidate nucleosides, the phosphonoamidate cognate class especially of acyclic nucleoside phosphonates (ANPs) lacks of such plethora of synthetic methodologies. 15 ANPs play a key role in the treatment of viral infections, and this class of compounds can be regarded as one of the most significant group of drugs in the antiviral field.…”