Inhibition of ß-Amyloid Aggregation through a Designed ß-Hairpin Peptide.
Langmuir
; 34(4): 1591-1600, 2018 01 30.
Article
en En
| MEDLINE
| ID: mdl-29284085
ABSTRACT
Designing peptide-based drugs to target the ß-sheet-rich toxic intermediates during the aggregation of amyloid-ß 1-42 (Aß1-42) has been a major challenge. In general, ß-sheet breaker peptides (BSBPs) are designed to complement the enthalpic interactions with the aggregating protein, and entropic effects are usually ignored. Here, we have developed a conformationally constrained cyclic BSBP by the use of an unnatural amino acid and a disulfide bond. We show that our peptide strongly inhibits the aggregation of Aß1-42 in a concentration-dependent manner. It stabilizes the random coil conformation of Aß1-42 monomers and inhibits the secondary structural transition to a ß-sheet-rich conformation which allows Aß1-42 to oligomerize in an ordered assembly during its aggregation. Our cyclic peptide also rescues the toxicity of soluble aggregates of Aß1-42 toward neuronal cells. However, it significantly loses its potency in the conformationally relaxed acyclic form. It appears that limiting the loss of conformational entropy of the BSBP ligand can play a very important role in the attainment of conformations for precise and tight binding, making them a potent inhibitor for Aß1-42 amyloidosis.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Péptidos
/
Péptidos Cíclicos
/
Péptidos beta-Amiloides
Idioma:
En
Revista:
Langmuir
Asunto de la revista:
QUIMICA
Año:
2018
Tipo del documento:
Article
País de afiliación:
India