Antiparallel β-Sheet as a Key Motif of Amyloid-β Inhibitor Designed via Topological Peptide Reprogramming

Abstract

Peptide inhibitor design targeting self-assembly of amyloid-β (Aβ) 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 Aβ aggregates. However, since the inherent flexibility of Aβ 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 Aβ 1–42 (Aβ42). The eleven-residue peptide scaffold P_a11 (¹⁴HQKLVNFAEDV²⁴) identified through the initial screening was dimerized via a disulfide bond. The dimerization stabilizes Aβ42 into higher order structures by promoting antiparallel β-sheet conformations, thereby significantly suppressing Aβ42 aggregation. Our approach underscores that modification in peptide connectivity would be a breakthrough for controlling the intrinsic flexibility of Aβ, surpassing the limitation in conventional, one-dimensional peptide building block.