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

초록

Peptide inhibitor design targeting self-assembly of amyloid-beta (A beta) 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 beta aggregates. However, since the inherent flexibility of A beta 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 beta 1-42 (A beta 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 beta 42 into higher order structures by promoting antiparallel beta-sheet conformations, thereby significantly suppressing A beta 42 aggregation. Our approach underscores that modification in peptide connectivity would be a breakthrough for controlling the intrinsic flexibility of A beta, surpassing the limitation in conventional, one-dimensional peptide building block.

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