β-Turn mimetic synthetic peptides as amyloid-β aggregation inhibitors

Aggregation of amyloid peptides results in severe neurodegenerative diseases. While the fibril structures of Aβ₄₀ and Aβ₄₂ have been described recently, resolution of the aggregation pathway and evaluation of potent inhibitors still remains elusive, in particular in view of the hairpin-region of Aβ₄₀. We here report the preparation of beta-turn mimetic conjugates containing synthetic turn mimetic structures in the turn region of Aβ₄₀ and Aβ_16-35, replacing 2 amino acids in the turn-region G25 - K28. The structure of the turn mimic induces both, acceleration of fibrillation and the complete inhibition of fibrillation, confirming the importance of the turn region on the aggregation. Replacing position G25-S26 provided the best inhibition effect for both beta-turn mimetics, the bicyclic BTD 1 and the aromatic TAA 2, while positions N27-K28 and V24-G25 showed only weaker or no inhibitory effects. When comparing different turn mimetics at the same position (G25-S26), conjugate 1a bearing the BTD turn showed the best inhibition of Aβ₄₀ aggregation, while 5-amino-valeric acid 4a showed the weakest effect. Thus there is a pronounced impact on fibrillation with the chemical nature of the embedded beta-turn-mimic: the conformationally constrained turns 1 and 2 lead to a significantly reduced fibrillation, even inhibiting fibrillation of native Aβ₄₀ when added in amounts down to 1/10, whereas the more flexible beta-turn-mimics 4-amino-benzoic acid 3a and 5-amino-valeric acid 4a lead to enhanced fibrillation. Toxicity-testing of the most successful conjugate showed only minor toxicity in cell-viability assays using the N2a cell line. Structural downsizing lead to the short fragment BTD/peptide Aβ_16-35 as inhibitor of the aggregation of Aβ₄₀, opening large potential for further small peptide based inhibitors.