Abstract
Alzheimer's disease is one of the devastating illnesses mankind is facing in the 21st century. The main pathogenic event in Alzheimer's disease is believed to be the aggregation of the β-amyloid (Aβ) peptides into toxic aggregates. Molecules that interfere with this process may act as therapeutic agents for the treatment of the disease. Use of recognition unit based peptidomimetics as inhibitors are a promising approach, as they exhibit greater protease stability compared to natural peptides. Here, we present peptidomimetic inhibitors of Aβ aggregation designed based on the KLVFF (P1) sequence that is known to bind Aβ aggregates. We improved inhibition efficiency of P1 by introducing multiple hydrogen bond donor-acceptor moieties (thymine/barbiturate) at the N-terminal (P2 and P3), and blood serum stability by modifying the backbone by incorporating sarcosine (N-methylglycine) units at alternate positions (P4 and P5). The peptidomimetics showed moderate to good activity in both inhibition and dissolution of Aβ aggregates as depicted by thioflavin assay, circular dichroism (CD) measurements and microscopy (TEM). The activity of P4 and P5 were studied in a yeast cell model showing Aβ toxicity. P4 and P5 could rescue yeast cells from Aβ toxicity and Aβ aggregates were cleared by the process of autophagy.
Highlights
Alzheimer’s disease is one of the devastating illnesses mankind is facing in the 21st century
The detailed mechanism of neurodegeneration encountered in Alzheimer’s disease (AD) is not entirely understood yet, several reports indicate that the fibrillar aggregation of b2amyloid (Ab) 36242 peptides and, in particular, highly toxic Ab42 play a key role in the pathogenesis of AD3–6
Several N-methylated peptides based on recognition sequence (KLVFF) have been systematically synthesized and analysed for their ability to function as fibrillar inhibitors and their effect on the Ab toxicity
Summary
Alzheimer’s disease is one of the devastating illnesses mankind is facing in the 21st century. Several N-methylated peptides based on recognition sequence (KLVFF) have been systematically synthesized and analysed for their ability to function as fibrillar inhibitors and their effect on the Ab toxicity. Introducing N-methyl analogs of natural amino acids at alternating positions of recognition peptide have shown promising activity in both inhibition and dissolution of Ab aggregates[29]. Designing hybrid peptide-peptoid based modulators targeting hydrogen bonding involved in b-sheet formation and subsequent elongation leading to fibrillar aggregates has not been addressed adequately in the literature. Developing hybrid peptide-peptoid based modulators aiming to target multiple phases of Ab42 aggregation would provide highly efficient inhibitors. Another potential approach is through enhancing the phenomenon of aggrephagy. Yeast model provides a platform to study the autophagy-based regulation[36]
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