Dual‐Functional Synthetic Linear and Cyclic Peptides with Anti‐Amyloid and Antimicrobial Activities for Alzheimer's Disease

Dual-functional peptides exhibiting both anti-amyloid and antimicrobial activities have attracted attention as promising candidates for Alzheimer's disease treatment. The advantage of these peptides lies in their ability to simultaneously target both the amyloid cascade hypothesis and the microbial infection hypothesis, in contrast to single-function inhibitors. However, most of the reported dual-functional peptides to date are natural peptides, and the development of synthetic peptides in this area remains limited. In this study, we propose two strategies to aid in the discovery of synthetic dual-functional peptides. We then report four distinct synthetic dual-functional peptides identified using these strategies, with the Aβ_1-40/Aβ_1-42 fibrillation system and common bacterial strains serving as a proof-of-concept platform. One strategy involves repurposing existing knowledge, while the other breaks from established conventions. Using the first strategy, we discovered a very short dual-functional linear peptide. With the second strategy, we identified a simple dual-functional cyclic peptide. Furthermore, by combining these two strategies, we developed a hybrid dual-functional peptide incorporating both linear and cyclic structures. We hope that our findings will contribute to the future discovery of more synthetic dual-functional peptides for treating Alzheimer's disease.