Inhibition of Amyloid Protein Aggregation Using Selected Peptidomimetics

Abstract

Aberrant protein aggregation leads to the formation of amyloid fibrils. This phenomenon is linked to the development of more than 40 irremediable diseases such as Alzheimer's disease, Parkinson's disease, type 2 diabetes, and cancer. Plenty of research efforts have been given to understanding the underlying mechanism of protein aggregation, associated toxicity, and the development of amyloid inhibitors. Recently, the peptidomimetic approach has emerged as a potential tool to modulate several protein‐protein interactions (PPIs). In this review, we discussed selected peptidomimetic‐based approaches for the modulation of important amyloid proteins (Islet Amyloid Polypeptide, Amyloid Beta, α‐synuclein, mutant p53, and insulin) aggregation. This approach holds a powerful platform for creating an essential stepping stone for the vital development of anti‐amyloid therapeutic agents.

The Strategies of Development of New Non-Toxic Inhibitors of Amyloid Formation

“…Synthetic and natural small molecules and peptides have been studied to inhibit insulin aggregation [ 161 , 162 , 163 , 164 , 165 ]. Some authors pay special attention to the consideration of the peptidomimetic approach for the modulation of important amyloid proteins (Aβ, α-synuclein, insulin, islet amyloid polypeptide and mutant p53) [ 166 ]. Unfortunately, many inhibitors cannot be used in medical practice due to potentially high toxicity to human cells.…”

Oncogenic R248W mutation induced conformational perturbation of the p53 core domain and the structural protection by proteomimetic amyloid inhibitor ADH-6

“…48 The a-helix mimetic inhibitors have been extensively studied and developed for inhibiting protein-protein interactions and protein aggregation, and these inhibitors include constrained peptides, proteomimetics, and small-molecule mimetics. 49,50 The basic idea behind the use of helix mimetics is to reproduce the side chain at residues i, i + 3/i + 4, and i + 7 of a natural a-helix. 51 Among these, proteomimetics, due to their ease of synthesis, higher solubility compared to constrained peptides, and the convenience of manipulating side-chain residues, exhibit promising potential for further development, and these include terphenyl-like molecules, oligobenzamides, and heterocyclic analogs.…”

Self-Blinking Thioflavin T for Super-resolution Imaging

“…A myloid and amyloid-like fibrils (e.g., peptide nanofibrils), formed from proteins and peptides, have emerged as important topics in recent years for various scientific endeavors in physics, 1,2 chemistry, 3,4 biology, 5,6 and medicine. 7,8 While some functional amyloids with beneficial biological activities have been studied, 9,10 disease-associated amyloid fibrils remain the focus of much current research.…”

“…Amyloid and amyloid-like fibrils (e.g., peptide nanofibrils), formed from proteins and peptides, have emerged as important topics in recent years for various scientific endeavors in physics, , chemistry, , biology, , and medicine. , While some functional amyloids with beneficial biological activities have been studied, , disease-associated amyloid fibrils remain the focus of much current research. For example, neurodegenerative diseases are age-related diseases for which pathophysiology is diverse, such as memory and cognitive impairments and reduced ability to move, speak, and breathe. , Alzheimer’s, Parkinson’s, and Huntington’s disease, all common neurodegenerative diseases, are associated with the misfolding of protein monomers and the formation of aggregated fibrous deposits in the brain. , α-Synuclein (α-Syn), a key protein implicated in Parkinson’s disease pathology, exhibits remarkable conformational plasticity, as it can adopt a wide range of structural conformations (oligomers, protofibrils, and fibrils). , Each α-Syn conformation displays distinct properties in terms of neurotoxicity, stability, and seeding and propagation ability .…”