Cyclic Phosphopantothenic Acid Prodrugs for Treatment of Pantothenate Kinase-Associated Neurodegeneration.
Giulio AucielloAnnalise Di MarcoOdalys Gonzalez PazSavina MalanconaSteven HarperMaria BeconiIlaria RossettiAlina CiammaichellaPaola FezzardiAndrea VecchiElena BracacelDaniel CiceroEdith MonteagudoDaniel ElbaumPublished in: Journal of medicinal chemistry (2020)
Mutations in the human PANK2 gene are implicated in neurodegenerative diseases such as pantothenate kinase-associated neurodegeneration (PKAN) and result in low levels of coenzyme-A (CoA) in the CNS due to impaired production of phosphopantothenic acid (PPA) from vitamin B5. Restoration of central PPA levels by delivery of exogenous PPA is a recent strategy to reactivate CoA biosynthesis in PKAN patients. Fosmetpantotenate is an oral PPA prodrug. We report here the development of a new PANk2-/- knockout model that allows CoA regeneration in brain cells to be evaluated and describe two new series of cyclic phosphate prodrugs of PPA capable of regenerating excellent levels of CoA in this system. A proof-of-concept study in mouse demonstrates the potential of this new class of prodrugs to deliver PPA to the brain following oral administration and confirms incorporation of the prodrug-derived PPA into CoA.
Keyphrases
- fatty acid
- end stage renal disease
- resting state
- induced apoptosis
- chronic kidney disease
- white matter
- cancer therapy
- endothelial cells
- ejection fraction
- gene expression
- newly diagnosed
- tyrosine kinase
- peritoneal dialysis
- prognostic factors
- signaling pathway
- blood brain barrier
- functional connectivity
- brain injury
- dna methylation
- copy number
- drug delivery
- cell proliferation
- multiple sclerosis
- cerebral ischemia
- cell cycle arrest
- transcription factor
- subarachnoid hemorrhage