Creation of Novel Cell-Penetrating Peptides for Intracellular Drug Delivery Using Systematic Phage Display Technology Originated from Tat Transduction Domain

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  • Kamada Haruhiko
    Laboratory of Pharmaceutical Proteomics, National Institute of Biomedical Innovation
  • Okamoto Takayuki
    Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Osaka University Department of Molecular Pathobiology, Mie University School of Medicine
  • Kawamura Maki
    Laboratory of Pharmaceutical Proteomics, National Institute of Biomedical Innovation Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Osaka University
  • Shibata Hiroko
    Laboratory of Pharmaceutical Proteomics, National Institute of Biomedical Innovation Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Osaka University
  • Abe Yasuhiro
    Laboratory of Pharmaceutical Proteomics, National Institute of Biomedical Innovation Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Osaka University
  • Ohkawa Akiko
    Laboratory of Pharmaceutical Proteomics, National Institute of Biomedical Innovation Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Osaka University
  • Nomura Tetsuya
    Laboratory of Pharmaceutical Proteomics, National Institute of Biomedical Innovation Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Osaka University
  • Sato Masaki
    Laboratory of Pharmaceutical Proteomics, National Institute of Biomedical Innovation Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Osaka University
  • Mukai Yohei
    Laboratory of Pharmaceutical Proteomics, National Institute of Biomedical Innovation Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Osaka University
  • Sugita Toshiki
    Laboratory of Pharmaceutical Proteomics, National Institute of Biomedical Innovation Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Osaka University
  • Imai Sunao
    Laboratory of Pharmaceutical Proteomics, National Institute of Biomedical Innovation Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Osaka University
  • Nagano Kazuya
    Laboratory of Pharmaceutical Proteomics, National Institute of Biomedical Innovation Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Osaka University
  • Tsutsumi Yasuo
    Laboratory of Pharmaceutical Proteomics, National Institute of Biomedical Innovation Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Osaka University
  • Nakagawa Shinsaku
    Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Osaka University
  • Mayumi Tadanori
    Department of Cell Therapeutics, Graduate School of Pharmaceutical Sciences, Kobe Gakuin University
  • Tsunoda Shin-ichi
    Laboratory of Pharmaceutical Proteomics, National Institute of Biomedical Innovation

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Abstract

Many biologically active proteins need to be delivered intracellularly to exert their therapeutic action inside the cytoplasm. Cell penetrating peptides (CPPs) have been developed to efficiently deliver a wide variety of cargo in a fully biological active form into a range of cell types for the treatment of multiple preclinical disease models. To further develop this methodology, we established a systematic approach to identify novel CPPs using phage display technology. Firstly, we screened a phage peptide library for peptides that bound to the cell membrane. Secondly, to assess functionality as intracellular carriers, we recombined cDNAs of binding peptides with protein synthesis inhibitory factor (PSIF) to create fusion proteins. Randomly chosen clones were cultured and expression of peptide-PSIF fusion proteins induced, followed by screening of protein synthesis activity in cells. Using this systematic approach, novel and effective CPPs were rapidly identified. We suggest that these novel cell-penetrating peptides can utilized as drug delivery tools for protein therapy or an analytical tool to study mechanisms of protein transduction into the cytoplasm.

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