Design of a Suicide Peptide Inhibitor for Alzheimer's Therapy
Date Issued
2010
Date
2010
Author(s)
Lin, Chih-Yun
Abstract
Recently we have reported an Aβ40 mutant peptide V24P, which has a Val-24→DPro substitution, can form a non-fibril amyloid-like β-aggregate at a high peptide concentration (60 μM). Interestingly, the cytotoxicity of Aβ40 can be decreased when Aβ40 is co-incubated with equal molar of V24P. In this study, a series of V24P derivatives were designed and synthesized. First, we removed the N-terminal hydrophilic part of V24P to produce a peptide named V24P(10-40) and removed the C-terminal hydrophobic part of V24P to produce another peptide named V24P(1-28). A similar amyloid-like β-aggregate was formed in 30 μM V24P(10-40). This peptide has a greater effect on decreasing Aβ40 toxicity than V24P. Another three shorter peptides V24P(13-36), V24P(16-33), V24P(19-30) were synthesized. They don’t have significant effect on decreasing Aβ40 toxicity, suggesting that the integrity of the hydrophobic segments on both sides of DPro-Gly turn is important. Based on our results, V24P(10-40) was singled out as the best candidate of peptide inhibitor. To avoid degradation by proteases and peptidases in body, we used D-form amino acids to synthesize another two peptides. One of them that has the same sequence of V24P(10-40) was encoded as d-V24P(10-40) and another one with the reversed sequence except the DPro-Gly segment was encoded as d-V24P(40-10). These two peptides had an inhibitory activity similar to that of V24P(10-40) and were resistant to the digestion of neprilysin which was thought as the key Aβ-degrading enzyme in brain. The effect of these peptides as peptide inhibitors in Alzheimer’s therapy will be examined in the future.
Subjects
Alzheimer’s disease
Amyloid-beta protein
cytotoxicity
inhibitor
SDGs
Type
thesis
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