Title
Inhibition of β-Amyloid Aggregation through a Designed β-Hairpin Peptide
Author
Anjali Jha, Mothukuri Ganesh Kumar, Hosahudya N. Gopi, Kishore M. Paknikar
Year
2018
Journal
Langmuir
Abstract
Designing peptide-based drugs to target the β-sheet-rich toxic intermediates during the aggregation of amyloid-β 1-42 (Aβ1-42) has been a major challenge. In general, β-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 Aβ1-42 in a concentration-dependent manner. It stabilizes the random coil conformation of Aβ1-42 monomers and inhibits the secondary structural transition to a β-sheet-rich conformation which allows Aβ1-42 to oligomerize in an ordered assembly during its aggregation. Our cyclic peptide also rescues the toxicity of soluble aggregates of Aβ1-42 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 Aβ1-42 amyloidosis.
Instrument
J-720
Keywords
Circular dichroism, Secondary structure, Aggregation, Biochemistry