Design of a Molecular Hybrid of Dual Peptide Inhibitors Coupled on AuNPs for Enhanced Inhibition of Amyloid β‐Protein Aggregation and Cytotoxicity

Aggregation of amyloid-β protein (Aβ) is a pathological hallmark of Alzheimer's disease (AD), so the inhibition of Aβ aggregation is an important strategy for the prevention and treatment of AD. Herein, we proposed to design molecular hybrids of peptide inhibitors by combining two peptide inhibitors, VVIA and LPFFD, into single sequences and examined their effects on Aβ42 aggregation and cytotoxicity. The hybrid peptides exhibit increased but moderate inhibitory activity as compared to their two precursors. By conjugating the peptides onto gold nanoparticles (AuNPs), however, the inhibition activity of the corresponding peptide@AuNPs against Aβ42 aggregation and cytotoxicity is greatly improved. Among them, VVIACLPFFD (VCD10)@AuNP is the most effective, which increases cell viability from 48% to 82% at a dosage as low as 0.1 nmol L-1 (NPs) or 40 nmol L-1 (peptide). The superior capacity of VCD10@AuNPs is considered due to its branched dual-inhibitor sequence, and its special surface orientation and conformation. These structural features promote its synergetic interactions with Aβ on AuNP surface, leading to strong inhibitions of Aβ oligomerization and fibrillation and the cytotoxicity caused by the aggregation species. The findings suggest that potent inhibitors can be derived by hybridization of multiple peptide inhibitors with the hybrid products coupled onto nanoparticles.