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Complex Polyamines: Unique Prion Disaggregating Compounds

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Among the candidate anti-prion chemotherapeutic agents identified to date, complex polyamines constitute the only class of compounds that possess the ability to remove pre-existing PrPSc molecules from infected cells. The potency of branched polyamines such as cationic dendrimers increases with the density of positive charges on their surface. Cationic dendrimers appear to accumulate together with PrPSc molecules in lysosomes, where the acidic environment facilitates dendrimer-mediated PrPSc disaggregation. Dendrimers can disaggregate a range of different amyloid proteins by interacting with specific epitopes on each protein. Studies with model peptides suggest that dendrimers may cause fiber breakage and capping of elongating fibers. Potential limitations to the development of dendrimers as therapeutic compounds for neurodegenerative disorders of protein misfolding such as prion diseases include poor bioavailability, limited spectrum of activity, and detrimental neurological side effects. A related group of compounds, lipopolyamines, are smaller molecules containing a lipophilic tail that may assist membrane targeting. Developing strategies to enable the safe delivery of potent complex polyamines to the central nervous system represents a critical avenue for future research.

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Keywords: PrPSc; Prion; branched polyamines; dendrimers

Document Type: Research Article

Publication date: 2009-11-01

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  • CNS & Neurological Disorders - Drug Targets aims to cover all the latest and outstanding developments on the medicinal chemistry, pharmacology, molecular biology, genomics and biochemistry of contemporary molecular targets involved in neurological and central nervous system (CNS) disorders e.g. disease specific proteins, receptors, enzymes, genes. Each issue of the journal will contain a series of timely in-depth reviews written by leaders in the field covering a range of current topics on drug targets involved in neurological and CNS disorders. As the discovery, identification, characterization and validation of novel human drug targets for neurological and CNS drug discovery continues to grow; this journal will be essential reading for all pharmaceutical scientists involved in drug discovery and development.
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