Rationally Designed Peptidomimetic Modulators of Aβ Toxicity in Alzheimer's Disease

• Published in: Scientific reports 2015-01, Vol.5 (1), p.8139, Article 8139
• Main Authors: Rajasekhar, K., Suresh, S. N., Manjithaya, Ravi, Govindaraju, T.
• Format: Article
• Language: English
• Subjects: 13; 14; 14/35; 14/63; 140/58; 147/143; 49; 49/75; 639/638; 639/638/309/2420; 64; Alzheimer Disease - blood; Alzheimer Disease - pathology; Amyloid beta-Peptides - antagonists & inhibitors; Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - toxicity; Amyloid beta-Peptides - ultrastructure; Autophagy - drug effects; Benzothiazoles; Biological Assay; Circular Dichroism; Drug Design; Green Fluorescent Proteins - metabolism; Humanities and Social Sciences; Humans; Kinetics; Microscopy, Fluorescence; Models, Biological; multidisciplinary; Peptide Fragments - antagonists & inhibitors; Peptide Fragments - chemistry; Peptide Fragments - toxicity; Peptide Fragments - ultrastructure; Peptidomimetics - pharmacology; Protein Aggregates - drug effects; Proteolysis - drug effects; Saccharomyces cerevisiae - drug effects; Science; Thiazoles - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep08139

Alzheimer's disease is one of the devastating illnesses mankind is facing in the 21 st 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.