Cyclic di-peptide in situ inhibited protein-aggregation.

ABSTRACT

An increasing number of neurodegenerative diseases seem to be associated with protein misfolding that often leads to misfolded protein aggregates with a ß-sheet conformation and accumulation in the brain which directly contributes to or modulates the associated pathology. Protein aggregation diseases like Huntington's disease results from the deposition of aggregated huntingtin proteins within the nucleus, transmissible prion encephalopathies occur due to extracellular deposition of pathogenic prion proteins whereas Alzheimer's disease from the accumulation of both extracellular ß-amyloid and intracellular hyperphosphorylated tau protein aggregates. In the generalized purpose, we have taken the core sequence of amyloid-ß (responsible for its aggregation) as the aggregating peptide (AP). Among the various emerging therapeutic approaches against aggregation-related degenerative diseases such as diminishing the monomeric precursor protein, inhibiting aggregation, or blocking aggregation-induced cellular toxicity pathways, we focussed on the strategy based on the inhibition of protein aggregation using rationally designed peptide inhibitors comprising both the recognition and ß-breaking component in the sequence. The "O â†’ N acyl migration" concept was used to form cyclic peptide in situ for the generation of a bent unit which may act as disruption moiety for the inhibition process. The kinetics of aggregation was characterized by various biophysical tools (ThT-assay, TEM, CD, and FTIR). Results implied that the designed inhibitor peptides (IP) might be valuable to inhibit all the related aggregated peptides.