Peptide-based amyloid-beta aggregation inhibitors

Abstract

Aberrant protein misfolding and accumulation is considered to be a major pathological pillar of neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. Aggregation of amyloid-β (Aβ) peptide leads to the formation of toxic amyloid fibrils and is associated with cognitive dysfunction and memory loss in Alzheimer's disease (AD). Designing molecules that inhibit amyloid aggregation seems to be a rational approach to AD drug development. Over the years, researchers have utilized a variety of therapeutic strategies targeting different pathways, extensively studying peptide-based approaches to understand AD pathology and demonstrate their efficacy against Aβ aggregation. This review highlights rationally designed peptide/mimetics, including structure-based peptides, metal-peptide chelators, stapled peptides, and peptide-based nanomaterials as potential amyloid inhibitors.

Fig. 1. Central hydrophobic core KLVFF-derived peptides and conjugates.

Fig. 2. Structure-based peptides derived from C-terminal region fragment VVIA of Aβ.

Fig. 3. The relationship between amyloidogenesis and the oxidative lipoidal membrane damage-mediated formation of HNE and MDA was schematically inferred. They contribute to apoptosis by inactivating proteins through the formation of Schiff bases. The amyloid precursor protein (APP) is proteolytically truncated by β- and γ-secretase proteases to produce Aβ (39 to 43). In parallel, under the influence of unaggregated soluble amyloid-β (Aβs), Cu²⁺ is reduced to Cu⁺, and Cu⁺ has a strong affinity for the ATCUN-type motif (His6/13/14) present in the Aβ peptides, creating the [Aβ/Cu⁺] redox complex. This event sets off oxidative stress (Fenton-type reaction), non-enzymatic lipo-hydroperoxidation by increased ROS production, especially ·OH. This process oxidizes lipid bilayers, including PUFAs, cholesterol, and other fatty acids, resulting in the production of harmful, highly reactive HNE, MDA, and other isoprostane by-products. HNE joined with Aβ and makes an HNE/Aβ-modified adduct. This adduct then helped fibrillogenesis by changing Aβ into nanofibrillary structures and, finally, mature Aβ-fibrils (AβFs). On the other hand, HNE and MDA react with the amino acid side chains of DNA, proteins, and enzymes. This creates Schiff base/Michael adducts, which are even more harmful to cells. In short, high levels of amyloid-β cause plasma membrane lysis and apoptosis by throwing off the balance of cellular homeostasis.

Fig. 4. Stapled peptides as Aβ aggregation inhibitors.

Fig. 5. Peptide/mimetics as amyloid beta inhibitors.

Fig. 6. Structure of nanosweeper CS–K_m–B_n (24) and CP-2 (25).

Fig. 7. The mechanism of action of peptide-based Aβ aggregation inhibitors: (A) Aβ oligomerization and fibrillary formation lead to neuronal loss; its role in ROS production and tau aggregations in the case of AD; (B) the role of peptide-based Aβ aggregation inhibitors in disrupting oligomerization and fibrillolysis.