A RaPID Macrocyclic Peptide That Inhibits the Formation of α-Synuclein Amyloid Fibrils.
Chembiochem
; 24(12): e202300320, 2023 06 15.
Article
en En
| MEDLINE
| ID: mdl-37186077
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.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Enfermedad de Parkinson
/
Alfa-Sinucleína
Límite:
Humans
Idioma:
En
Año:
2023
Tipo del documento:
Article