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The ‘ O ‐acyl isopeptide method’ for the synthesis of difficult sequence‐containing peptides: application to the synthesis of Alzheimer's disease‐related amyloid β peptide (Aβ) 1–42
Author(s) -
Sohma Youhei,
Hayashi Yoshio,
Kimura Maiko,
Chiyomori Yousuke,
Taniguchi Atsuhiko,
Sasaki Masato,
Kimura Tooru,
Kiso Yoshiaki
Publication year - 2005
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/psc.649
Subject(s) - peptide , chemistry , acylation , sequence (biology) , acyl group , residue (chemistry) , solubility , peptide synthesis , combinatorial chemistry , acyl chloride , peptide sequence , intramolecular force , stereochemistry , biochemistry , organic chemistry , chloride , catalysis , alkyl , gene
An efficient ‘ O ‐acyl isopeptide method’ for the synthesis of difficult sequence‐containing peptides was applied successfully to the synthesis of amyloid β peptide (Aβ) 1–42 via a water‐soluble O ‐acyl isopeptide of Aβ1–42, i.e. ‘26‐ O ‐acyl isoAβ1–42’ ( 6 ). This paper describes the detailed synthesis of Aβ1–42 focusing on the importance of resin selection and the analysis of side reactions in the O ‐acyl isopeptide method. Protected ‘26‐ O ‐acyl isoAβ1–42’ peptide resin was synthesized using 2‐chlorotrityl chloride resin with minimum side reactions in comparison with other resins and deprotected crude 26‐ O ‐acyl isoAβ1–42 was easily purified by HPLC due to its relatively good purity and narrow elution with reasonable water solubility. This suggests that only one insertion of the isopeptide structure into the sequence of the 42‐residue peptide can suppress the unfavourable nature of its difficult sequence. The migration of O ‐acyl isopeptide to intact Aβ1–42 under physiological conditions (pH 7.4) via O N intramolecular acyl migration reaction was very rapid and no other by‐product formation was observed while 6 was stable under storage conditions. These results concluded that our strategy not only overcomes the solubility problem in the synthesis of Aβ1–42 and can provide intact Aβ1–42 efficiently, but is also applicable in the synthesis of large difficult sequence‐containing peptides at least up to 50 amino acids. This synthesis method would provide a biological evaluation system in Alzheimer's disease research, in which 26‐ O ‐acyl isoAβ1–42 can be stored in a solubilized form before use and then rapidly produces intact Aβ1–42 in situ during biological experiments. Copyright © 2005 European Peptide Society and John Wiley & Sons, Ltd.