Anti‐parallel β‐Sheet as a Key Motif of Amyloid‐β Inhibitor Designed via Topological Peptide Reprogramming

Abstract

Aggregation of amyloidogenic intrinsically disordered proteins (IDPs) such as amyloid-β (Aβ) is associated with the pathogenesis of Alzheimer's disease (AD). Peptide inhibitors targeting Aβ peptide represents a promising strategy to disrupt its pathogenic self-assembly. Conventional inhibitor design primarily mimics repetitive sequences found in fibrillar Aβ assemblies. However, since the structural dynamics of Aβ involves in the early-stage oligomerization, its conformational flexibility should be considered in sequence-based design principle. Herein, we introduce topological reprogramming of peptide inhibitors to induce the structural transformation in pathogenic Aβ 1–42 (Aβ42). The eleven-residue peptide scaffold Pa11 (14HQKLVNFAEDV24) identified through the initial screening was dimerized via a disulfide bond. The dimerization stabilizes local Aβ42 structures by promoting anti-parallel β-sheet conformations in the scaffolds, thereby significantly suppressing Aβ42 aggregation. Our approach underscores that conformational features of IDPs can be modulated through the modification in peptide connectivity, suggesting a novel strategy for Aβ-targeted peptide building block.

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