A RaPID Macrocyclic Peptide That Inhibits the Formation of -Synuclein Amyloid Fibrils

There is considerable interest in drug discovery targeting the aggregation of alpha-synuclein (alpha Syn) since this molecular process is closely associated with Parkinson's disease. However, inhibiting alpha Syn aggregation remains a major challenge because of its highly dynamic nature which makes it difficult to form a stable binding complex with a drug molecule. Here, by exploiting Random non-standard Peptides Integrated Discovery (RaPID) system, we identified a macrocyclic peptide, BD1, that could interact with immobilized alpha Syn and inhibit the formation of fibrils. Furthermore, improving the solubility of BD1 suppresses the co-aggregation with alpha Syn fibrils while it kinetically inhibits more effectively without change in their morphology. We also revealed the molecular mechanism of kinetic inhibition, where peptides bind to fibril ends of alpha Syn, thereby preventing further growth of fibrils. These results suggest that our approach for generating non-standard macrocyclic peptides is a promising approach for developing potential therapeutics against neurodegeneration.