Synthesis of an O-acyl isopeptide by using native chemical ligation in an aqueous solvent system

Authors

  • Hiroyuki Kawashima,

    1. Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto, Japan
    2. Department of Pharmaceutical Manufacturing Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto, Japan
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  • Tomomi Kuruma,

    1. Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto, Japan
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  • Masayuki Yamashita,

    1. Department of Pharmaceutical Manufacturing Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto, Japan
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  • Youhei Sohma,

    Corresponding author
    1. Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto, Japan
    2. Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
    • Correspondence to: Youhei Sohma, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. E-mail: ysohma@mol.f.u-tokyo.ac.jp

      Correspondence to: Kenichi Akaji, Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 60-8412, Japan. E-mail: akaji@mb.kyoto-phu.ac.jp

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  • Kenichi Akaji

    Corresponding author
    1. Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto, Japan
    • Correspondence to: Youhei Sohma, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. E-mail: ysohma@mol.f.u-tokyo.ac.jp

      Correspondence to: Kenichi Akaji, Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 60-8412, Japan. E-mail: akaji@mb.kyoto-phu.ac.jp

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Abstract

O-Acyl isopeptides, in which the N-acyl linkage on the hydroxyamino acid residue (e.g. Ser and Thr) is replaced by an O-acyl linkage, generally suppress unfavorable aggregation properties derived from the corresponding parent peptides. Here, we report the synthesis of an O-acyl isopeptide of 34-mer pyroGlu-ADan (2), a component of amyloid deposits in hereditary familial Danish dementia, by using native chemical ligation. Native chemical ligation of pyroGlu1-ADan(1-21)-SCH2CH2SO3Na+ (3) and Cys22-O-acyl isopeptide (4), in which the amino group of the Ser29 residue at the isopeptide moiety was protected by an allyloxycarbonyl group, proceeded well in an aqueous solvent to yield a ligated O-acyl isopeptide (5). Subsequent disulfide bond formation and deprotection of the allyloxycarbonyl group followed by HPLC purification gave 2 with a reasonable overall yield. 2 was converted to the parent peptide 1 via an O-to-N acyl migration reaction. The sequential method, namely (i) native chemical ligation of the O-acyl isopeptide, (ii) HPLC purification as the O-acyl isopeptide form, and (iii) O-to-N acyl migration into the desired polypeptide, would be helpful to solve problems with HPLC purification of hydrophobic polypeptides in the process of chemical protein synthesis. Copyright © 2014 European Peptide Society and John Wiley & Sons, Ltd.

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