Synthesis of Aβ(1-42) and its derivatives with improved efficiency

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40 Citations (Scopus)

Abstract

It has been proved that the principal component of senile plaques is aggregates of β-amyloid peptide (Aβ) in cases of one of the most common forms of age-related neurodegenerative disorders, Alzheimer's disease (AD). Although the synthetic methods for the synthesis of Aβ peptides have been developed since their first syntheses, Aβ[1-42] is still problematic to prepare. The highly hydrophobic composition of Aβ[1-42] results in aggregation between resin-bound peptide chains or intrachain aggregation which leads to a decrease in the rates of deprotection and repetitive incomplete coupling reactions during 9-flurenylmethoxycarbonyl (Fmoc) synthesis. In order to avoid aggregation and/or disrupt internal aggregation during stepwise Fmoc solid phase synthesis and to improve the quality of crude products, several attempts have been made. Since highly pure Aβ peptides in large quantities are used in biological experiments, we wanted to develop a method for a rational synthesis of human Aβ[1-42] with high purity and adequate yield. This paper reports a convenient methodology with a novel solvent system for the synthesis of Aβ[1-42], its N-terminally truncated derivatives Aβ[4-42] and Aβ[5-42], and Aβ[1-421 labeled with 7-amino-4-methyl-3-coumarinylacetic acid (AMCA) at the N-terminus using Fmoc strategy. The use of 10% anisole in Dimethylformamide/ Dichloromethane (DMF/DCM) can substantially improve the purity and yield of crude Aβ[1-42] and has been shown to be an optimal coupling condition for the synthesis of Aβ[1-42]. Anisole is a cheap and simple aid in the synthesis of 'difficult sequences' where other solvents are less successful in the prevention of aggregation during the synthesis.

Original languageEnglish
Pages (from-to)94-99
Number of pages6
JournalJournal of Peptide Science
Volume13
Issue number2
DOIs
Publication statusPublished - Feb 1 2007

Keywords

  • Alzheimer's disease
  • Beta-amyloid
  • Difficult sequences
  • Labeling of beta-amyloid
  • Neurodegeneration
  • Synthesis

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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