In:
ChemMedChem, Wiley, Vol. 7, No. 3 ( 2012-03-05), p. 515-522
Abstract:
Neurotoxic Aβ42 oligomers are believed to be the main cause of Alzheimer’s disease. Previously, we found that the C‐terminal fragments (CTFs), Aβ(30–42) and Aβ(31–42) were the most potent inhibitors of Aβ42 oligomerization and toxicity in a series of Aβ( x –42) peptides ( x =28–39). Therefore, we chose these peptides as leads for further development. These CTFs are short (12–13 amino acids) hydrophobic peptides with limited aqueous solubility. Our first attempt to attach hydrophilic groups to the N terminus resulted in toxic peptides. Therefore, we next incorporated N ‐methyl amino acids, which are known to increase the solubility of such peptides by disrupting the β‐sheet formation. Focusing on Aβ(31–42), we used a two‐step N ‐methyl amino acid substitution strategy to study the structural factors controlling inhibition of Aβ42‐induced toxicity. First, each residue was substituted by N ‐Me‐alanine ( N ‐Me‐A). In the next step, in positions where substitution produced a significant effect, we restored the original side chain. This strategy allowed exploring the role of both side chain structure and N ‐Me substitution in inhibitory activity. We found that the introduction of an N ‐Me amino acid was an effective way to increase both the aqueous solubility and the inhibitory activity of Aβ(31–42). In particular, N ‐Me amino acid substitution at position 9 or 11 increased the inhibitory activity relative to the parent peptide. The data suggest that inhibition of Aβ42 toxicity by short peptides is highly structure‐specific, providing a basis for the design of new peptidomimetic inhibitors with improved activity, physicochemical properties, and metabolic stability.
Type of Medium:
Online Resource
ISSN:
1860-7179
,
1860-7187
DOI:
10.1002/cmdc.201100584
Language:
English
Publisher:
Wiley
Publication Date:
2012
detail.hit.zdb_id:
2209649-8
SSG:
15,3
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