The Anthelmintic Drug Niclosamide and Its Analogues Activate the Parkinson's Disease Associated Protein Kinase PINK1.

Mutations in PINK1, which impair its catalytic kinase activity, are causal for autosomal recessive early-onset Parkinson's disease (PD). Various studies have indicated that the activation of PINK1 could be a useful strategy in treating neurodegenerative diseases, such as PD. Herein, it is shown that the anthelmintic drug niclosamide and its analogues are capable of activating PINK1 in cells through the reversible impairment of the mitochondrial membrane potential. With these compounds, for the first time, it is demonstrated that the PINK1 pathway is active and detectable in primary neurons. These findings suggest that niclosamide and its analogues are robust compounds for the study of the PINK1 pathway and may hold promise as a therapeutic strategy in PD and related disorders.

Aryloxy Pivaloyloxymethyl Prodrugs as Nucleoside Monophosphate Prodrugs.

Intracellular phosphorylation of therapeutic nucleoside analogues into their active triphosphate metabolites is a prerequisite for their pharmacological activity. However, the initial phosphorylation of these unnatural nucleosides into their monophosphate derivatives can be a rate-limiting step in their activation. To address this, we herein report the development of the aryloxy pivaloyloxymethyl prodrugs (POMtides) as a novel and effective nucleoside monophosphate prodrug technology and its successful application to the anticancer nucleoside analogue 5-fluoro-2'-deoxyuridine (FdUR).

Aryloxy Triester Phosphoramidates as Phosphoserine Prodrugs: A Proof of Concept Study.

The specific targeting of protein-protein interactions by phosphoserine-containing small molecules has been scarce due to the dephosphorylation of phosphoserine and its charged nature at physiological pH, which hinder its uptake into cells. To address these issues, we herein report the synthesis of phosphoserine aryloxy triester phosphoramidates as phosphoserine prodrugs that are enzymatically metabolized to release phosphoserine. This phosphoserine-masking approach was applied to a phosphoserine-containing inhibitor of 14-3-3 dimerization, and the generated prodrugs exhibited improved pharmacological activity. Collectively, this provided a proof of concept that the masking of phosphoserine with biocleavable aryloxy triester phosphoramidate masking groups is a viable intracellular delivery system for phosphoserine-containing molecules. Ultimately, this will facilitate the discovery of phosphoserine-containing small-molecule therapeutics.

Phosphotyrosine prodrugs: design, synthesis and anti-STAT3 activity of ISS-610 aryloxy triester phosphoramidate prodrugs.

Unmasked phohate groups of phosphotyrosine-containing molecules carry two negative charges at physiological pH, which compromise their (passive) cellular uptake. Also, these phosphate groups are often cleaved off by phosphatases. Together, these ultimately limit the pharmacological efficacy of the phosphotyrosine-containing compounds. To address these drawbacks, we herein present the application of the aryloxy triester phosphoramidate prodrug technology, a monophosphate prodrug technology, to the phosphotyrosine-containing compound ISS-610-Met, an analogue of the anticancer STAT3 dimerization inhibitor ISS-610. Our data shows that the generated ISS-610-Met prodrugs exhibited enhanced pharmacological activity and inhibition of STAT3 downstream signaling compared to the parent compound ISS-610-Met and the known STAT3 dimerization inhibitor ISS-610. These encouraging results provide a compelling proof of concept for the potential of the aryloxy triester phosphoramidate prodrug technology in the discovery of novel therapeutics that contain phosphotyrosine and its phospho mimics.

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.

Nucleoside Phosphate and Phosphonate Prodrug Clinical Candidates.

Nucleoside monophosphates and monophosphonates have been known for a long time to exert favorable pharmacological effects upon intracellular delivery. However, their development as drug molecules has been hindered by the inherent poor druglike properties of the monophosphate and monophosphonate groups. These include inefficient cellular uptake and poor in vivo stability, with this latter drawback being most relevant to monophosphates than monophosphonates. To address these limitations, numerous monophosphate and monophosphonate prodrug strategies have been developed and applied in the discovery of nucleoside monophosphate and monophosphonate prodrugs that can treat viral infections and cancer. The approval of sofosbuvir, a nucleoside monophosphate prodrug, highlighted the success to be had by employing these prodrug technologies in the discovery of nucleotide therapeutics. In this Miniperspective, we discuss the different key monophosphate and monophosphonate nucleoside prodrugs that entered clinical development, some of which may in the future be approved to treat various human diseases.