Synthesis of the isopeptide of amyloid β peptide using an <em>O-</em>acyl isodipeptide unit in the Boc SPPS — ASN Events
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Synthesis of the isopeptide of amyloid β peptide using an O-acyl isodipeptide unit in the Boc SPPS (#56)

Taku Yoshiya 1 , Takahiro Maruno 2 , Tsuyoshi Uemura 1 , Shigeru Kubo 1 , Yoshiaki Kiso 3 , Youhei Sohma 4 , Kumiko Yoshizawa-Kumagaye 1 , Yuji Kobayashi 2 , Yuji Nishiuchi 1 5
  1. Peptide Institute, Inc., Ibaraki, Osaka, Japan
  2. Graduate School of Engineering, Osaka Univ., Suita, Osaka, Japan
  3. Laboratory of Peptide Science, Nagahama Institute of Bio-Science and Technology, Nagahama, Japan
  4. Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
  5. Graduate School of Science, Osaka Univ., Toyonaka, Japan

An “O-acyl isopeptide method” was developed for the synthesis of peptides containing difficult sequences.1  The introduction of an O-acyl isopeptide bond instead of a native N-acyl peptide bond at a hydroxyamino acid residue (e.g. Ser, Thr) drastically changes the secondary structure of the native peptide. Such an “O-acyl isopeptide” is generally stable under the acidic conditions or in the TFA-form lyophilized powder. The target peptide is, however, immediately released from the isopeptide via an O-to-N intramolecular acyl migration reaction under the neutral conditions. Moreover, with the aid of the O-acyl isodipeptide unit, O-acyl isopeptides could be readily synthesized by the Fmoc SPPS.

In general, the Boc SPPS is known to be superior to the Fmoc SPPS with regard to the preparation efficacy of the difficult sequence-containing peptides.2  Thus, we conceived that the combination of the O-acyl isopeptide method and the Boc SPPS would be a potentially powerful methodology for the synthesis of difficult peptides. Toward routine preparation of the isopeptide by Boc chemistry, here we report a novel O-acyl isodipeptide unit and its application for synthesizing an O-acyl isopeptide of amyloid β peptide 1-423  with an automated peptide synthesizer. The isopeptide of amyloid β peptide 1-42 was synthesized successfully without any considerable side reactions associated with use of the O-acyl isopeptide method. Additionally, we confirmed that the synthesized isopeptide is present as a monomeric form under the acidic conditions by means of an analytical ultracentrifugation.

  1. Sohma, Y. et al. Chem. Commun. 2004, 124.
  2. Beyermann, M. and Bienert, M. Tetrahedron Lett. 1992, 33, 3745.
  3. Sohma, Y. et al. Biopolymers 2007, 88, 253.