Unnatural foldamers as inhibitors of Aβ aggregation stabilizing the Aβ helix.

Protein aggregation is a critical factor in the development and progression of several human diseases, including Alzheimer's disease (AD), Huntington's disease, Parkinson's disease, and type 2 diabetes. Among these conditions, AD is recognized as the most prevalent progressive neurodegenerative disorder, characterized by the accumulation of amyloid-beta (Aβ) peptides. Neuronal toxicity is likely driven by soluble oligomeric intermediates of the Aβ peptide, which are thought to play a central role in the cascade leading to neuronal dysfunction and cognitive decline. In response, numerous therapeutic strategies have been developed to inhibit Aβ oligomerization, as this is believed to delay the formation of Aβ protofibrils. Traditional research has focused on discovering small molecules or peptides that antagonize Aβ oligomerization. However, recent studies have explored an alternative approach-developing ligands that stabilize the Aβ peptide in its α-helical conformation. This stabilization is thought to alter the peptide's natural aggregation kinetics, shifting it away from toxic oligomer formation and toward less harmful states. Crucially, by maintaining Aβ in this α-helical form, these ligands have been shown to rescue the peptide's associated cytotoxicity, offering a promising mechanism to mitigate the detrimental effects of Aβ in AD. While challenges remain, including treatment costs and side effects like ARIA (amyloid-related imaging abnormalities), anti-Aβ drug development represents a major advancement in Alzheimer's research and therapeutic options. This brief review aims to highlight the development and potential of these α-helix-stabilizing ligands as antagonists of Aβ aggregation, focusing on their interactions with Aβ and how these compounds induce and maintain secondary structural changes in the Aβ peptide. Notably, this innovative strategy holds promise beyond Aβ-related pathology, as the fundamental principles could be applied to other amyloidogenic proteins implicated in various amyloid-related diseases, potentially broadening the scope of therapeutic intervention for multiple neurodegenerative conditions.