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

Area of Science:

• Biochemistry
• Neuroscience
• Drug Discovery

Background:

• Misfolded amyloid beta (Aβ) peptide accumulation outside nerve cells is a primary cause of Alzheimer's disease (AD).
• Blocking early Aβ aggregation steps is a promising therapeutic strategy for AD.
• Current strategies face challenges in effectively inhibiting Aβ self-assembly.

Purpose of the Study:

• To design and synthesize novel breaker peptides derived from Aβ sequences.
• To investigate the mechanism of in-situ self-cyclization for disrupting Aβ aggregation.
• To evaluate the efficacy of these peptides in preventing and disassembling amyloid fibrils.

Main Methods:

• Development of synthetic peptides with modified glutamic acid at position 18 (Glu-OBn) to induce turns.
• Biophysical assays including Thioflavin T (ThT) assay, Transmission Electron Microscopy (TEM), and Congo-red birefringence.
• Spectroscopic analyses using Circular Dichroism (CD) and Fourier-Transform Infrared (FTIR) spectroscopy to study conformational changes.

Main Results:

• Designed breaker peptides successfully undergo in-situ cyclization, forming structural turns.
• These peptides effectively inhibit and disrupt the formation of amyloid fibrils.
• Conformational changes indicative of β-sheet disruption were observed via CD and FTIR spectroscopy.

Conclusions:

• Synthetic breaker peptides can inhibit and disrupt amyloid beta (Aβ) aggregation.
• The in-situ cyclization mechanism is effective in preventing toxic peptide assembly.
• These peptides hold potential for therapeutic applications in Alzheimer's disease and other protein aggregation disorders.