Promising anti-amyloid behavior of cationic pyridylphenylene dendrimers: Role of structural features and mechanism of action

Abstract Misfolding and aggregation of amyloidogenic proteins are responsible for the onset of neurodegenerative diseases. This makes studies directed towards prevention of these processes of particular importance. In this paper we report that cationic pyridylphenylene dendrimers of the second (G2), third (G3) and fourth (G4) generations act as effective suppressors of the amyloid aggregation of the full-length ovine prion protein (PrP). The dendrimers are able to inhibit both the formation of the most toxic soluble oligomers and amyloid fibrils. Dendrimer binding prevents the structural conversion of PrP and further protein fibrillation. The effect is dependent on the dendrimer generation with G4 being the most potent. Importantly, after the treatment with the dendrimers, PrP does not induce the pathological conformational changes in native PrP, indicating the loss of amyloidogenic properties. The cell viability assay reveals the dependence on the cell line and the dendrimer generation used. The observed fundamental principles of the dendrimer interaction with PrP helped us to elucidate the protective effect of the dendrimers and to suggest the potential mechanism of the dendrimer action. Noteworthy, the dendrimers preserve their protective effect regardless of the aggregation conditions applied, indicating the important role of their structural features, e.g. rigidity and permanent charge, in anti-amyloid behavior.