Influence of Surface Groups on Poly(propylene imine) Dendrimers Antiprion Activity

Prion diseases are characterized by the accumulation of PrP^Sc, an aberrantly folded isoform of the host protein PrP^C. Specific forms of synthetic molecules known as dendrimers are able to eliminate protease-resistant PrP^Sc in both an intracellular and in vitro setting. The properties of a dendrimer which govern this ability are unknown. We addressed the issue by comparing the in vitro antiprion ability of numerous modified poly­(propylene-imine) dendrimers, which varied in size, structure, charge, and surface group composition. Several of the modified dendrimers, including an anionic glycodendrimer, reduced the level of protease resistant PrP^Sc in a prion strain-dependent manner. This led to the formulation of a new working model for dendrimer/prion interactions which proposes dendrimers eliminate PrP^Sc by destabilizing the protein and rendering it susceptible to proteolysis. This ability is not dependent on any particular charge of dendrimer, but does require a high density of reactive surface groups