Polyamine conjugation as a new strategy to target amyloid aggregation in the framework of Alzheimer’s disease

Spermine conjugates 2-6, carrying variously decorated 3,S-dibenzylidenepiperidin-4-one as bioactive motives, were designed to direct antiaggregating properties into mitochondria, using a polyamine functionality as the vehicle tool. The study confirmed mitochondrial import of the catechol derivative 2, which displayed effective antiaggregating activity and neuroprotective effects against A beta-induced toxicity. Notably, a key functional role for the polyamine motif in A beta molecular recognition was also unraveled. This experimental readout, which was supported by in silico studies, gives important new insight into the polyamine's action. Hence, we propose polyamine conjugation as a promising strategy for the development of neuroprotectant leads that may contribute to decipher the complex picture of A beta toxicity.