Design of hybrid peptide foldamers as antimicrobial agents and Aβ aggregation inhibitors

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder marked by progressive memory loss and is the leading cause of dementia, with projections indicating that 139 million people will be affected by 2050 (World Alzheimer Report 2013-2050). The disease places a significant emotional burden on families and one of the pathological features of the disease is identified to be the aggregation of disordered polypeptides, particularly beta-amyloid (Aβ) fibrils. Mutations in the Amyloid Precursor Protein (APP) lead to an excessive accumulation of insoluble Aβ due to the actions of γ- and β-secretases, which have proven challenging as drug targets due to their membrane-bound nature. A promising therapeutic strategy focuses on inhibiting the formation of soluble Aβ oligomers, especially Aβ42. The Aβ42 peptide contains the Amino Terminal Cu(II) and Ni(II) (ATCUN) binding motif, highlighting the role of copper dyshomeostasis in AD and its relationship with increased oxidative stress from Aβ42. Recent developments in antibody-based therapies targeting amyloid plaques have further spurred interest in small molecules and peptide inhibitors for Aβ aggregation. Our lab's previous findings identified a 15-residue α-peptide and ααγ hybrid peptide that inhibit the aggregation of soluble Aβ42 and can disintegrate existing aggregates. In continuation, we have designed and synthesized peptides incorporating the ATCUN motif aimed at both copper retrieval and disruption of Aβ aggregation as a dual diagnostic and therapeutic approach. Preliminary results indicate these peptides bind Cu2+ and inhibit amyloid aggregation. In addition, these designed peptides showed specific antimicrobial activity against Acinetobacter baumannii, warranting further investigation.