Complex polyamines: unique prion disaggregating compounds

Abstract

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 PrP(Sc) 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 PrP(Sc) molecules in lysosomes, where the acidic environment facilitates dendrimer-mediated PrP(Sc) 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.

Fig. (1)

Hypothetical mechanisms of PrP^Sc formation and polyamine-mediated clearance in cells (A) Schematic representation of cell biology of PrP^Sc formation. The biosynthesis of PrP^C proceeds through the secretory pathway, which produces mature PrP^C molecules that are tethered to the extracellular leaflet of the plasma membrane. Eventually, PrP^C molecules are endocytosed through a process apparently mediated by lipoprotein receptor related protein 1 (LRP1) [32, 33]. The pathogenic conformational change of PrP^C into PrP^Sc molecules may require interaction with endogeneous lipid and polyanionic cofactors [4], probably occurs either on the cell surface or within the endocytic pathway, and ultimately results in accumulation of PrP^Sc molecules in lysosomes [25]. (B) Schematic representation of the cell biology of polyamine-mediated PrP^Sc clearance. Complex polyamines such as dendrimers appear to be internalized through the endocytic pathway, and eventually become co-localized with PrP^Sc molecules within lysosomes [10]. The acidic environment of this compartment appears to facilitate polyamine-medicated PrP^Sc denaturation, and resident hydrolases may also facilitate the clearance of PrP^Sc molecules from lysosomes.