RESUMEN
Ubiquitin phosphorylation by the mitochondrial protein kinase PTEN-induced kinase 1 (PINK1), upon mitochondrial depolarization, is an important intermediate step in the recycling of damaged mitochondria via mitophagy. As mutations in PINK1 can cause early-onset Parkinson's disease (PD), there has been a growing interest in small-molecule activators of PINK1-mediated mitophagy as potential PD treatments. Herein, we show that N6-substituted adenosines, such as N6-(2-furanylmethyl)adenosine (known as kinetin riboside) and N6-benzyladenosine, activate PINK1 in HeLa cells and induce PINK1-dependent mitophagy in primary mouse fibroblasts. Interestingly, pre-treatment of HeLa cells and astrocytes with these compounds inhibited elevated ubiquitin phosphorylation that is induced by established mitochondrial depolarizing agents, carbonyl cyanide m-chlorophenyl-hydrazine and niclosamide. Together, this highlights N6-substituted adenosines as progenitor PINK1 activators that could potentially be developed, in the future, as treatments for aged and sporadic PD patients who have elevated phosphorylated ubiquitin levels in the brain.
Asunto(s)
Mitofagia , Ubiquitina , Humanos , Animales , Ratones , Fosforilación , Ubiquitina/metabolismo , Células HeLa , Proteínas Quinasas/metabolismo , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
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.
Asunto(s)
Amidas/farmacología , Ácidos Fosfóricos/farmacología , Fosfoserina/antagonistas & inhibidores , Profármacos/farmacología , Amidas/síntesis química , Amidas/química , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Ácidos Fosfóricos/síntesis química , Ácidos Fosfóricos/química , Fosforilación/efectos de los fármacos , Fosfoserina/metabolismo , Profármacos/síntesis química , Profármacos/químicaRESUMEN
PINK1 is a ubiquitously expressed mitochondrial serine/threonine protein kinase that has emerged as a key player in mitochondrial quality control. This protein kinase came to prominence in the mid-2000s, when PINK1 mutations were found to cause early onset Parkinson's disease (PD). As most of the PD-related mutations occurred in the kinase domain and impaired PINK1's catalytic activity, it was suggested that small molecules that activated PINK1 would maintain mitochondrial quality control and, as a result, have neuroprotective effects. Working on this hypothesis, a few small-molecule PINK1 activators that offer critical insights and distinct approaches for activating PINK1 have been discovered. Herein, we briefly highlight the discovery of these small molecules and offer insight into the future development of small-molecule PINK1 activators as potential treatments for PD.
Asunto(s)
Activadores de Enzimas/farmacología , Proteínas Quinasas/metabolismo , Animales , Células HeLa , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Mitocondrias/metabolismo , Enfermedad de Parkinson/enzimologíaRESUMEN
Niclosamide is an anthelmintic drug that has been used for over 50 years mainly to treat tapeworm infections. However, with the increase in drug repurposing initiatives, niclosamide has emerged as a true hit in many screens against various diseases. Indeed, from being an anthelmintic drug, it has now shown potential in treating Parkinson's disease, diabetes, viral and microbial infections, as well as various cancers. Such diverse pharmacological activities are a result of niclosamide's ability to uncouple mitochondrial phosphorylation and modulate a selection of signaling pathways, such as Wnt/ß-catenin, mTOR and JAK/STAT3, which are implicated in many diseases. In this highlight, we discuss the plethora of diseases that niclosamide has shown promise in treating.