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A Two-Step Strategy for Structure-Activity Relationship Studies of N-Methylated A[beta]42 C-Terminal Fragments as A[beta]42 Toxicity Inhibitors

Li, Huiyuan ; Zemel, Reeve ; Lopes, Dahabada H. J ; Monien, Bernhard H ; Bitan, Gal

ChemMedChem, 2012-03, Vol.7 (3), p.515-522 [Periódico revisado por pares]

Weinheim: Wiley Subscription Services, Inc

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  • Título:
    A Two-Step Strategy for Structure-Activity Relationship Studies of N-Methylated A[beta]42 C-Terminal Fragments as A[beta]42 Toxicity Inhibitors
  • Autor: Li, Huiyuan ; Zemel, Reeve ; Lopes, Dahabada H. J ; Monien, Bernhard H ; Bitan, Gal
  • Assuntos: Amino acids ; Peptides ; Toxicity
  • É parte de: ChemMedChem, 2012-03, Vol.7 (3), p.515-522
  • Notas: ObjectType-Article-2
    SourceType-Scholarly Journals-1
    ObjectType-Feature-1
    content type line 23
  • Descrição: Neurotoxic A[beta]42 oligomers are believed to be the main cause of Alzheimer's disease. Previously, we found that the C-terminal fragments (CTFs), A[beta](30-42) and A[beta](31-42) were the most potent inhibitors of A[beta]42 oligomerization and toxicity in a series of A[beta](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 Nterminus 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 [beta]-sheet formation. Focusing on A[beta](31-42), we used a two-step N-methyl amino acid substitution strategy to study the structural factors controlling inhibition of A[beta]42-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 A[beta](31-42). In particular, N-Me amino acid substitution at position9 or 11 increased the inhibitory activity relative to the parent peptide. The data suggest that inhibition of A[beta]42 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. [PUBLICATION ABSTRACT]
  • Editor: Weinheim: Wiley Subscription Services, Inc
  • Idioma: Inglês;Alemão
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  • Realização: ABCD-USP USP   Logos de Redes Sociais: Freepik

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