Antiparallel <i>β</i> ‐Sheet as a Key Motif of Amyloid‐ <i>β</i> Inhibitor Designed via Topological Peptide Reprogramming

Abstract Peptide inhibitor design targeting self‐assembly of amyloid‐ β (A β ) represents a promising strategy for suppressing the pathogenic mechanism of Alzheimer's disease (AD). Conventional approaches have primarily mimicked repetitive sequences found in fibrillar structures of A β aggregates. However, since the inherent flexibility of A β structures promotes the structural changes in the early‐stage oligomerization, a structural modulation should be considered in the design of peptide inhibitors. Herein, we introduce topological reprogramming of peptides to control the structural transformation in pathogenic A β 1–42 (A β 42). The eleven‐residue peptide scaffold P a11 ( 14 HQKLVNFAEDV 24 ) identified through the initial screening was dimerized via a disulfide bond. The dimerization stabilizes A β 42 into higher order structures by promoting antiparallel β ‐sheet conformations, thereby significantly suppressing A β 42 aggregation. Our approach underscores that modification in peptide connectivity would be a breakthrough for controlling the intrinsic flexibility of A β , surpassing the limitation in conventional, one‐dimensional peptide building block.