Study on the Efficiency and Interaction Mechanism of a Decapeptide Inhibitor of β‑Amyloid Aggregation

This paper reports an active decapeptide inhibitor (RR: RYYAAFFARR) of β-amyloid (Aβ_1–40) aggregation. Traditional inhibitors target the hydrophobic core of Aβ (Aβ_16–20) and were designed based on the single hydrophobic interaction. RR was designed to target an extended region (Aβ_11–23), which contains three important regions of Aβ_1–40. RR exhibits stronger binding affinity for Aβ_1–40 (K_D = 1.10 μM) than the known β-sheet breaker LPFFD (K_D = 156 μM). Our study shows that RR inhibited the fibrillation of Aβ_1–40 by nearly 75% at an equimolar concentration, and that a 1:4 ratio of Aβ_1–40/ RR almost completely inhibited fibrillation. The interaction mechanism was also investigated by changing the ionic strength or the structure of RR. The results revealed that RR binds to Aβ_1–40 because of its strong affinity for Aβ_11–23, which is mainly driven by hydrophobic and electrostatic interactions and hydrogen bonding.