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Click Peptide Concept: O-Acyl Isopeptide of Islet Amyloid Polypeptide as a Nonaggregative Precursor Molecule

Authors

  • Dr. Taku Yoshiya,

    1. Kyoto Pharmaceutical University, Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, Yamashina-ku, Kyoto 607-8412 (Japan), Fax: (+81) 75-595-4787
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  • Ayano Higa,

    1. Kyoto Pharmaceutical University, Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, Yamashina-ku, Kyoto 607-8412 (Japan), Fax: (+81) 75-595-4787
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  • Naoko Abe,

    1. Kyoto Pharmaceutical University, Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, Yamashina-ku, Kyoto 607-8412 (Japan), Fax: (+81) 75-595-4787
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  • Fukue Fukao,

    1. Kyoto Pharmaceutical University, Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, Yamashina-ku, Kyoto 607-8412 (Japan), Fax: (+81) 75-595-4787
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  • Tomomi Kuruma,

    1. Kyoto Pharmaceutical University, Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, Yamashina-ku, Kyoto 607-8412 (Japan), Fax: (+81) 75-595-4787
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  • Yuki Toda,

    1. Kyoto Pharmaceutical University, Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, Yamashina-ku, Kyoto 607-8412 (Japan), Fax: (+81) 75-595-4787
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  • Prof. Dr. Youhei Sohma,

    Corresponding author
    1. Kyoto Pharmaceutical University, Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, Yamashina-ku, Kyoto 607-8412 (Japan), Fax: (+81) 75-595-4787
    • Kyoto Pharmaceutical University, Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, Yamashina-ku, Kyoto 607-8412 (Japan), Fax: (+81) 75-595-4787
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  • Prof. Dr. Yoshiaki Kiso

    Corresponding author
    1. Kyoto Pharmaceutical University, Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, Yamashina-ku, Kyoto 607-8412 (Japan), Fax: (+81) 75-595-4787
    • Kyoto Pharmaceutical University, Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, Yamashina-ku, Kyoto 607-8412 (Japan), Fax: (+81) 75-595-4787
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Abstract

The O-acyl isopeptide (1) of islet amyloid polypeptide (IAPP), which contains an ester moiety at both Ala8-Thr9 and Ser19-Ser20, was prepared by sequential segment condensation based on the O-acyl isopeptide method. Isopeptide 1 possessed nonaggregative properties, retaining its random coil structure under the acidic conditions; this suggests that the insertion of the O-acyl isopeptide structures in IAPP suppressed aggregation of the molecule. As a result of the rapid O-to-N acyl shift of 1 under neutral pH, in situ-formed IAPP adopted a random-coil structure at the start of the experiment, and then underwent conformational change to α-helix/β-sheet mixed structures as well as aggregation. The click peptide strategy with the nonaggregative precursor molecule 1 could be a useful experimental tool to identify the functions of IAPP, by overcoming the handling difficulties that arise from IAPP's intense and uncontrollable self-assembling nature.

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