Zinc sequestering dual-functional molecules for bimodal targeting inhibition of Aβ42-aggregation.

Amyloidosis encompasses diseases characterized by abnormal protein folding and assembly, leading to deposition of insoluble amyloid fibrils that cause cellular dysfunction and death. Metal ions represent physiologically relevant environmental factors influencing amyloid-β (Aβ) peptide conformation and aggregation. Zinc ions (Zn2+) interact with Aβ-a pathogenic hallmark-and accumulate in senile plaques within Alzheimer's disease (AD) brains. Consequently, developing bifunctional agents that inhibit Zn2+-mediated Aβ aggregation could constitute a promising mechanism-based strategy. In this work, we integrate terpyridine into our molecular design to exploit its Zn2+-chelating capability, thereby inhibiting Zn2+-mediated Aβ aggregation. Furthermore, to address photodynamic therapy limitations, we developed novel naphthalene-derived dual-function molecules through structural optimization of 1,4-dimethylnaphthalene scaffolds. These dual-function molecules target Aβ42 aggregates and release singlet oxygen, which oxidizes amino acid residues, reduces Aβ42 hydrophobicity, and ultimately inhibits and depolymerizes Zn2+-mediated Aβ42 aggregates. This work pioneers a concept using specially designed molecules that integrate a terpyridine unit for Zn2+ chelation with an endoperoxide moiety as a targeted singlet oxygen reservoir. This dual-function design enables the simultaneous inhibition of Zn2+-mediated Aβ42 aggregation and oxidation-induced depolymerization of the aggregates.