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

Area of Science:

• Biochemistry
• Neuroscience
• Drug Discovery

Background:

• Alzheimer's disease (AD) pathogenesis involves the self-assembly of amyloid-beta (Aβ) peptides into toxic aggregates.
• Conventional peptide inhibitors often mimic fibrillar Aβ structures but overlook the dynamic nature of early-stage oligomerization.
• The inherent flexibility of Aβ structures contributes to pathogenic transformations, necessitating inhibitors that modulate structural dynamics.

Purpose of the Study:

• To introduce a novel strategy of topological reprogramming for designing peptide inhibitors against Aβ aggregation.
• To control the structural transformation of pathogenic amyloid-beta 1-42 (Aβ42) using engineered peptides.
• To investigate the efficacy of dimerized peptide scaffolds in stabilizing Aβ42 and preventing its aggregation.

Main Methods:

• Identification of an eleven-residue peptide scaffold (P_a11: ¹⁴HQKLVNFAEDV²⁴) through screening.
• Dimerization of the peptide scaffold via a disulfide bond to create a topologically reprogrammed inhibitor.
• Assessment of the dimerized peptide's effect on Aβ42 structural transformation and aggregation kinetics.

Main Results:

• The dimerized peptide scaffold (P_a11) effectively stabilizes Aβ42 into higher-order structures.
• Stabilization is achieved by promoting antiparallel β-sheet conformations within Aβ42.
• Significant suppression of Aβ42 aggregation was observed in the presence of the designed peptide inhibitor.

Conclusions:

• Topological reprogramming of peptides offers a breakthrough approach to control the intrinsic flexibility of Aβ.
• This method overcomes limitations of conventional one-dimensional peptide inhibitors.
• Engineered peptide connectivity provides a powerful strategy for developing novel therapeutics against Alzheimer's disease.