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.

Auciello, G., Di Marco, A., Gonzalez Paz, O., Malancona, S., Harper, S., Beconi, M., et al. (2020). Cyclic phosphopantothenic acid prodrugs for treatment of pantothenate kinase-associated neurodegeneration. JOURNAL OF MEDICINAL CHEMISTRY, 63(24), 15785-15801 [10.1021/acs.jmedchem.0c01531].

Cyclic phosphopantothenic acid prodrugs for treatment of pantothenate kinase-associated neurodegeneration

Cicero D.;
2020-01-01

Abstract

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.
2020
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore CHIM/08 - CHIMICA FARMACEUTICA
English
Animals; Blood-Brain Barrier; Brain; Coenzyme A; Cyclization; Disease Models, Animal; Half-Life; Hepatocytes; Lipid Droplets; Mice; Mice, Inbred C57BL; Mice, Knockout; Pantothenate Kinase-Associated Neurodegeneration; Pantothenic Acid; Prodrugs; Structure-Activity Relationship
Auciello, G., Di Marco, A., Gonzalez Paz, O., Malancona, S., Harper, S., Beconi, M., et al. (2020). Cyclic phosphopantothenic acid prodrugs for treatment of pantothenate kinase-associated neurodegeneration. JOURNAL OF MEDICINAL CHEMISTRY, 63(24), 15785-15801 [10.1021/acs.jmedchem.0c01531].
Auciello, G; Di Marco, A; Gonzalez Paz, O; Malancona, S; Harper, S; Beconi, M; Rossetti, I; Ciammaichella, A; Fezzardi, P; Vecchi, A; Bracacel, E; Cicero, D; Monteagudo, E; Elbaum, D
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/274763
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