Inhibition of β-Amyloid Aggregation through a Designed β-Hairpin Peptide.

Designing peptide-based drugs to target the β-sheet-rich toxic intermediates during the aggregation of amyloid-β 1-42 (Aβ) has been a major challenge. In general, β-sheet breaker peptides (BSBPs) are designed to complement the enthalpic interactions with the aggregating protein, and entropic effects are usually ignored. Here, we have developed a conformationally constrained cyclic BSBP by the use of an unnatural amino acid and a disulfide bond. We show that our peptide strongly inhibits the aggregation of Aβ in a concentration-dependent manner. It stabilizes the random coil conformation of Aβ monomers and inhibits the secondary structural transition to a β-sheet-rich conformation which allows Aβ to oligomerize in an ordered assembly during its aggregation. Our cyclic peptide also rescues the toxicity of soluble aggregates of Aβ toward neuronal cells. However, it significantly loses its potency in the conformationally relaxed acyclic form. It appears that limiting the loss of conformational entropy of the BSBP ligand can play a very important role in the attainment of conformations for precise and tight binding, making them a potent inhibitor for Aβ amyloidosis.