Peptidomimetics Made by Tail-to-Side Chain One Component Peptide Stapling Inhibit Alzheimer’s Amyloid-β Fibrillogenesis

Alzheimer’s disease (AD) is the most common form of dementia affecting the elderly population worldwide. Despite enormous efforts and considerable advancement in research, no therapeutic agents have come to light to date. However, many peptide-based and small molecule inhibitors interact efficiently with Amyloid-β (A) peptide and alter its aggregation pathway. On the other hand, stapled peptides have been developed mainly to stabilize the -helix conformation and study protein-protein interactions. -Sheet stabilization or destabilization by stapled peptides is not explored enough. Herein, we describe the generation of a library of “tail-to-side chain” stapled peptides via lactamization and their first application as modulators of A1-40 self-association and fibrillogenesis. It also disrupts the preformed fibrillar aggregates into nontoxic species. Their stability in the presence of proteolytic enzymes is increased due to stapling. Therefore, the stapled peptides thus formed can be useful as potent amyloid aggregation inhibitors and pave a therapeutic pathway for combating amyloid-related diseases. Also, it may help in gaining insight into the process of aggregation.