Lambrechts, R (Roald) (2012) ORIENTATION ON PHARMACOLOGICAL INTERVENTION IN PANTOTHENATE KINASE-ASSOCIATED NEURODEGENERATION :Rational design, synthesis and therapeutic potential of TBTP-pantetheine, a novel pantethine derivative. thesis, Medicine.
Full text available on request.Abstract
Pantothenate kinase-associated neurodegeneration (PKAN) is a devastating, lethal and currently incurable neurodegenerative disease that features movement disorders and dysarthria. The molecular defect causing the disease is located in pantothenate kinase 2 (PANK2), the rate-limiting enzyme in the biosynthesis of Coenzyme A. In earlier papers, it has been shown that the pantothenate analogue pantethine, the dimer of pantetheine, can drastically ameliorate the symptoms of this disease and restore the CoA levels in a Drosophila model of PKAN. However, pantethine is known to show considerable chemical instability in serum, limiting bioavailability and cellular uptake, and consequently therapeutic value. In this report, the synthesis of a novel pantetheine derivative – 4-thiobutyltriphenylphosphonium pantetheine (TBTP-pantetheine) – is described, as well as the exploration of its pharmacological properties and therapeutic potential. It is shown that TBTP-pantetheine is stable in water at 37 °C, and that the compound is able to rescue the S2 cell and Drosophila model of PKAN at lower concentrations than pantethine. TBTP-pantetheine shows a higher affinity for membranes than pantethine, which promotes its bioavailability and cellular uptake. This may be the explanation for the enhanced rescue potential observed in the PKAN models. This derivatisation may prove to be a step towards overcoming crucial obstacles associated with a pantethine-based therapy for PKAN.
| Item Type: | Thesis (Thesis) |
|---|---|
| Supervisor name: | SUPERVISION: and Sibon, Prof. dr. O.C.M. and DEPARTMENT OF RADIATION AND STRESS CELL BIOLOGY, UMCG |
| Faculty: | Medical Sciences |
| Date Deposited: | 25 Jun 2020 10:45 |
| Last Modified: | 25 Jun 2020 10:45 |
| URI: | https://umcg.studenttheses.ub.rug.nl/id/eprint/679 |
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