In-situ side-chain peptide cyclization as a breaker strategy against the amyloid aggregating peptide

Accumulation and deposition of misfolded amyloid beta (A beta) peptide outside the nerve cells are one of the major causes of Alzheimer's disease (AD). To date, one of the promising therapeutic strategies for AD is to block the early steps associated with the aggregation of A beta peptide. We have developed synthetic breaker peptides derived from the original A beta sequences that undergo self-cyclization in situ. We have focussed and replaced Val-18 (of A beta) by side-chain modified glutamic acid (Glu-OBn) to generate adequate turn through in-situ peptide cyclization to disrupt the beta-sheet structure of A beta. The disruption of amyloid fibril formation and the mechanism of the 'inhibition of aggregation' were studied by various biophysical methods, such as ThT-assay, TEM, Congo-red birefringence study. CD and FTIR spectroscopy were used to characterize the conformational change during the aggregation process. Results suggest that designed breaker peptides may be useful to inhibit and disrupt not only A beta peptide but related peptides that undergo aggregation.

Automated summary

Researchers have developed a breaker peptide that disrupts the beta-sheet structure of Aβ and prevents its aggregation into amyloid fibrils through in-situ cyclization. Various biophysical methods were used to study the mechanism of action, indicating that the designed breaker peptides may be useful for inhibiting and disrupting not only Aβ peptides, but related peptides that undergo aggregation.