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

Although inhibition of α-synuclein aggregation is an appealing approach for the prevention of this neurodegenerative pathology, the development of a binder has been yet challenging because of the disordered nature of α-synuclein. Here, by means of the RaPID system, we discovered a macrocycle inhibitor for the formation of α-synuclein aggregation at low stoichiometries.

Abstract

There is considerable interest in drug discovery targeting the aggregation of α-synuclein (αSyn) since this molecular process is closely associated with Parkinson's disease. However, inhibiting αSyn 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 αSyn and inhibit the formation of fibrils. Furthermore, improving the solubility of BD1 suppresses the co-aggregation with αSyn 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 αSyn, 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.

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