Structure-Based Peptide Inhibitor Design of Amyloid-β Aggregation

Many human neurodegenerative diseases are associated with amyloid fibril formation. Inhibition of amyloid formation is of importance for therapeutics of the related diseases. However, the development of selective potent amyloid inhibitors remains challenging. Here based on the structures of amyloid beta (A beta) fibrils and their amyloid-forming segments, we designed a series of peptide inhibitors using RosettaDesign. We further utilized a chemical scaffold to constrain the designed peptides into beta-strand conformation, which significantly improves the potency of the inhibitors against A beta aggregation and toxicity. Furthermore, we show that by targeting different A beta segments, the designed peptide inhibitors can selectively recognize different species of A beta. Our study developed an approach that combines the structure-based rational design with chemical modification for the development of amyloid inhibitors, which could be applied to the development of therapeutics for different amyloid-related diseases.