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

被引:44
作者
Zarandi, Marta [1 ]
Soos, Katalin [1 ]
Fulop, Livia [1 ]
Bozso, Zsolt [1 ]
Datki, Zsolt [1 ]
Toth, Gabor K. [1 ]
Penke, Botond [1 ]
机构
[1] Univ Szeged, Dept Med Chem, H-6720 Szeged, Hungary
关键词
beta-amyloid; synthesis; difficult sequences; neurodegeneration; Alzheimer's disease; labeling of beta-amyloid;
D O I
10.1002/psc.801
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
It has been proved that the principal component of senile plaques is aggregates of P-amyloid peptide (AP) 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 A beta peptides have been developed since their first syntheses, A beta[1-42] is still problematic to prepare. The highly hydrophobic composition of A beta [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-flurenyImethoxycarbonyl (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 AP peptides in large quantities are used in biological experiments, we wanted to develop a method for a rational synthesis of human A beta[1-42] with high purity and adequate yield. This paper reports a convenient methodology with a novel solvent system for the synthesis of A beta[1-42], its N-terminally truncated derivatives A beta[4-42] and A beta[5-42], and A beta[1-42] labeled with 7-amino-4-methyl-3-coumalinylacetic 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 A beta[1-42] and has been shown to be an optimal coupling condition for the synthesis of A beta[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. Copyright (c) 2006 European Peptide Society and John Wiley & Sons, Ltd.
引用
收藏
页码:94 / 99
页数:6
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