Abstract
Inhibition of fibrillation process and disaggregation of mature fibrils using small peptide are the promising remedial strategies to combat neurodegenerative diseases. However, designing peptide-based drugs to target β-sheet-rich amyloid has been a major challenge. The current work describes, for the first time, the amyloid inhibitory potential of the two short peptides (selected on the basis of predisposition of their amino acid residues toward β-sheet formation) using combination of biophysical, imaging methods, and docking approaches. Results showed that peptides employed different mechanisms to inhibit the amyloid fibrillation. Furthermore, they were also effective in blocking the amyloid fibrillation pathway. In contrary to the insulin fibrillar mesh, significantly less fibrillar species appeared in the presence of peptides, as confirmed by transmission electron microscopy. Circular dichroism analysis indicated that although peptides did not stabilize the native state of insulin, they inhibited amyloid aggregation by reducing the formation of β-sheet rich structures. Hemolytic assay revealed the non-hemolytic nature of the species formed when insulin was co-incubated with the peptides. Therefore, despite the inherent potential to form β-sheet structure, these peptides inhibited the amyloid formation and potentially can be used as therapeutics for the treatment of amyloid-related diseases.
Highlights
Aggregation and disaggregation of proteins and peptides are at the center of interest in various scientific fields, spanning from nanosciences, membrane technology, gelation, drug delivery to drug discovery, and medicine
Peptide inhibitory effects got saturated. These results indicated that both peptides inhibited the insulin fibrillation, and their effects were dose-dependent
We presented evidence that short peptides despite having inherent predisposition to form βsheet structure, are able to inhibit the formation of cross βsheet rich structure during insulin fibrillation
Summary
Aggregation and disaggregation of proteins and peptides are at the center of interest in various scientific fields, spanning from nanosciences, membrane technology, gelation, drug delivery to drug discovery, and medicine. In addition to proteins associated with amyloid diseases, non-pathological proteins form amyloid fibrils with characteristics, such as fibrillar morphology, biochemical properties, similar to those of the amyloidogenic proteins This suggests the inherent property of polypeptides to form amyloid fibrils (Chiti et al, 2003; Chiti and Dobson, 2006; Siddiqi et al, 2016). We have chosen to test the effect of two designed peptides P4 (ValIle-Phe-Tyr-Thr) and P5 (Val-Val-Val-Val-Val) (Supplementary Figure S1) These peptides were selected on the basis of the predisposition of their amino acid residues to acquire a particular secondary structure (based on their frequencies of being found in particular types of secondary structure). The anti-aggregation action of P4 and P5 against insulin fibrillation may possibly deliver an enhanced vision of structurally similar compounds against the aggregation of protein and might prove useful in designing suitable inhibitors which may act against amyloid associated disorders
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