32 research outputs found
Fosmetpantotenate (RE-024), a phosphopantothenate replacement therapy for pantothenate kinase-associated neurodegeneration: Mechanism of action and efficacy in nonclinical models
<div><p>In cells, phosphorylation of pantothenic acid to generate phosphopantothenic acid by the pantothenate kinase enzymes is the first step in coenzyme A synthesis. Pantothenate kinase 2, the isoform localized in neuronal cell mitochondria, is dysfunctional in patients with pantothenate kinase-associated neurodegeneration. Fosmetpantotenate is a phosphopantothenic acid prodrug in clinical development for treatment of pantothenate kinase-associated neurodegeneration, which aims to replenish phosphopantothenic acid in patients. Fosmetpantotenate restored coenzyme A in short-hairpin RNA pantothenate kinase 2 gene-silenced neuroblastoma cells and was permeable in a blood-brain barrier model. The rate of fosmetpantotenate metabolism in blood is species-dependent. Following up to 700 mg/kg orally, blood exposure to fosmetpantotenate was negligible in rat and mouse, but measurable in monkey. Consistent with the difference in whole blood half-life, fosmetpantotenate dosed orally was found in the brains of the monkey (striatal dialysate) but was absent in mice. Following administration of isotopically labeled-fosmetpantotenate to mice, ~40% of liver coenzyme A (after 500 mg/kg orally) and ~50% of brain coenzyme A (after 125 ÎĽg intrastriatally) originated from isotopically labeled-fosmetpantotenate. Additionally, 10-day dosing of isotopically labeled-fosmetpantotenate, 12.5 ÎĽg, intracerebroventricularly in mice led to ~30% of brain coenzyme A containing the stable isotopic labels. This work supports the hypothesis that fosmetpantotenate acts to replace reduced phosphopantothenic acid in pantothenate kinase 2-deficient tissues.</p></div
Effects of 1 ÎĽM fosmetpantotenate TID for 5 consecutive days in shRNA PanK2 knockdown human neuroblastoma cells.
<p>(A) Intracellular CoA concentrations, n = 3. (B) Western blot densitometry values. β-actin was used for normalization. Two experiments in duplicate. Two sided t-test; *p ≤0.05, **p ≤0.01, ***p ≤0.001. Gel images can be found in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0192028#pone.0192028.s002" target="_blank">S2 Fig</a>.</p
PPA and total PA in mouse and rat blood.
<p>Concentration-versus-time plots of PPA and PA after a single oral administration of fosmetpantotenate at 100, 300, or 700 mg/kg in CD1 mice (N = 4 per time point) or Sprague Dawley rats (N = 3 per time point).</p
Mean half—Life of fosmetpantotenate and diastereomers after incubation with blood from various species at 37°C for 60 min<sup>a</sup>.
<p>Mean half—Life of fosmetpantotenate and diastereomers after incubation with blood from various species at 37°C for 60 min<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0192028#t002fn001" target="_blank"><sup>a</sup></a>.</p
Scheme depicting the different metabolic paths to CoA formation from either pantothenic acid or fosmetpantotenate.
<p>Scheme depicting the different metabolic paths to CoA formation from either pantothenic acid or fosmetpantotenate.</p
Discovery by organism based high-throughput screening of new multi-stage compounds affecting <i>Schistosoma mansoni</i> viability, egg formation and production
<div><p>Schistosomiasis, one of the most prevalent neglected parasitic diseases affecting humans and animals, is caused by the Platyhelminthes of the genus <i>Schistosoma</i>. Schistosomes are the only trematodes to have evolved sexual dimorphism and the constant pairing with a male is essential for the sexual maturation of the female. Pairing is required for the full development of the two major female organs, ovary and vitellarium that are involved in the production of different cell types such as oocytes and vitellocytes, which represent the core elements of the whole egg machinery. Sexually mature females can produce a large number of eggs each day. Due to the importance of egg production for both life cycle and pathogenesis, there is significant interest in the search for new strategies and compounds not only affecting parasite viability but also egg production. Here we use a recently developed high-throughput organism-based approach, based on ATP quantitation in the schistosomula larval stage of <i>Schistosoma mansoni</i> for the screening of a large compound library, and describe a pharmacophore-based drug selection approach and phenotypic analyses to identify novel multi-stage schistosomicidal compounds. Interestingly, worm pairs treated with seven of the eight compounds identified show a phenotype characterized by defects in eggshell assemblage within the ootype and egg formation with degenerated oocytes and vitelline cells engulfment in the uterus and/or oviduct. We describe promising new molecules that not only impair the schistosomula larval stage but also impact juvenile and adult worm viability and egg formation and production <i>in vitro</i>.</p></div
Apparent in vitro permeability of diastereomers of fosmetpantotenate, PA, and PPA in a blood—Brain barrier permeability model using co-cultured porcine brain endothelial cells and rat astrocytes<sup>a</sup>.
<p>Apparent in vitro permeability of diastereomers of fosmetpantotenate, PA, and PPA in a blood—Brain barrier permeability model using co-cultured porcine brain endothelial cells and rat astrocytes<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0192028#t003fn001" target="_blank"><sup>a</sup></a>.</p
Fosmetpantotenate, PPA, and total PA in monkey blood.
<p>Concentrations of fosmetpantotenate, PPA, and PA after a single oral administration of fosmetpantotenate in cynomolgus monkeys at 300 mg/kg (N = 2).</p
Fosmetpantotenate, PPA, and total PA in monkey blood and brain striatal dialysate.
<p>Single oral administration to cynomolgus monkeys (100 and 300 mg/kg).</p
Four PPA-containing metabolites of fosmetpantotenate detected in monkey blood after a single oral administration of 300 mg/kg.
<p>Four PPA-containing metabolites of fosmetpantotenate detected in monkey blood after a single oral administration of 300 mg/kg.</p