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.