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ELUCIDATION OF THE MECHANISM OF EFFECTIVE MEMBRANE PERMEATION OF BUFORIN 2 AND ITS APPLICATION TO VECTOR FOR INTRACELLULAR DRUG DELIVERY

Research Project

Project/Area Number 14572091
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field 医薬分子機能学
Research InstitutionKyoto University

Principal Investigator

MATSUZAKI Katsumi  KYOTO UNIVERSITY, GRADUATE SCHOOL OF PHARMACEUTICAL SCIENCE, PROFESSOR, 薬学研究科, 教授 (00201773)

Project Period (FY) 2002 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥3,900,000 (Direct Cost: ¥3,900,000)
Fiscal Year 2004: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2003: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2002: ¥1,500,000 (Direct Cost: ¥1,500,000)
KeywordsANTIMICROBIAL PEPTIDE / BUFORIN 2 / TRANSLOCATION / ELECTROSTATIC REPULSION / PEPTIDE-LIPID SUPRAMOLECULAR COMPLEX PORE / MAGAININ 2 / AMPHIPATHIC HELIX / CELL PENETRATING PEPTIDE / プロリン / シス-トランス互変異性 / 濃度依存性 / 曲率 / 細胞膜透過 / 薬物キャリアー / ベクター / 細胞内移行 / ドラックデリバリー / 細胞毒性
Research Abstract

MORE THAN 500 ANTIMICROBIAL PEPTIDES HAVE BEEN DISCOVERED FROM VARIOUS ANIMALS INCLUDING HUMAN AND PLANTS. THESE PEPTIDES ARE NOW RECOGNIZED TO PLAY AN IMPORTANT ROLE IN INNATE IMMUNITY. MANY ANTIMICROBIAL PEPTIDES, LIKE MAGAININ 2 ISOLATED FROM XENOPUS LAEVIS, TARGET BACTERIAL CELL MEMBRANES, EXERTING CYTOTOXICITY BY PERMEABILIZING THEM. IN CONTRAST, BUFORIN 2 ISOLATED FROM BUFO BUFO GARGARIZANS EFFECTIVELY CROSS MEMBRANES WITHOUT PERMEABILIZATION, KILLING BACTERIA BY BINDING DNA AND RNA.
THE AIMS OF THIS STUDY ARE 1)TO ELUCIDATE THE MECHANISM OF THE EFFECTIVE TRANSLOCATION OF BUFORIN 2 AND 2)TO APPLY THIS UNIQUE PROPERTY TO INTRACELLULAR DRUG DELIVERY.
1)MECHANISM OF TRANSLOCATION : BUFORIN 2 TRANSLOCATES ACROSS LIPID BILAYERS BY A MECHANISM ESSENTIALLY THE SAME AS THAT OF MAGAININ 2, I.E. VIA THE FORMATION OF A TRANSIENT PEPTIDE-LIPID SUPRAMOLECULAR COMPLEX PORE. THE SHORT AMPHIPATHIC HELIX (RESIDUES 5-21) FORMED BY THE PRESENCE OF PROLINE11 CONTAINS MANY POSITIVE CHARGES. THEREFORE, THE ELECTROSTATIC REPULSION EXTREMELY DESTABILIZES THE PORE, MINIMIZING MEMBRANE PERMEABILIZATION.
2)INTRACELLULAR DRUG DELIVERY : BUFORIN 2 DERIVATIVES WITH THE TEXAS RED DYE AS A DRUG MODEL AT THE N- OR C-TERMINUS WERE SYNTHESIZED, AND THEIR INTERACTIONS WITH HUMAN CELL LINES (HELA AND TM12) WERE INVESTIGATED. THESE PEPTIDES TEMPERATURE-INDEPENDENTLY PENETRATED CELLS EVEN IN THE PRESENCE OF A METABOLIC INHIBITOR, FURTHERMORE, THE TOXICITIES OF THESE PEPTIDES WERE VERY LOW. THUS, BUFORIN 2 IS A PROMISING CANDIDATE OF A VECTOR FOR INTRACELLULAR DRUG DELIVERY.
FINALLY, THE AIMS OF THIS STUDY COULD BE ACHIEVED BY THE AID OF THIS GRANT.

Report

(4 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • Research Products

    (10 results)

All 2004 2003 2002 Other

All Journal Article (8 results) Publications (2 results)

  • [Journal Article] Membrane translocation mechanism of the antimicrobial peptide buforin 22004

    • Author(s)
      S, Kobayashi et al.
    • Journal Title

      Biochemistry 43・49

      Pages: 15610-15616

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Role of positional hydrophobicity in the leishmanicidal activity of magainin 22004

    • Author(s)
      E.Guerrero et al.
    • Journal Title

      Antimicrob.Agents Chemother. 48・8

      Pages: 2980-2986

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] MEMBRANE TRANSLOCATION MECHANISM OF THE ANTIMICROBIAL PEPTIDE BUFORIN 22004

    • Author(s)
      S.KOBAYASHI et al.
    • Journal Title

      BIOCHEMISTRY 43-49

      Pages: 15610-15616

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] ROLE OF POSITIONAL HYDROPHOBICITY IN THE LEISHMANICIDAL ACTIVITY OF MAGAININ 22004

    • Author(s)
      E.GUERRERO et al.
    • Journal Title

      ANTIMICROB.AGENTS CHEMOTHER. 48-8

      Pages: 2980-2986

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Translocation of analogues of the antimicrobial peptides magainin and buforin across human cell membranes2003

    • Author(s)
      K.Takeshima et al.
    • Journal Title

      J.Biol.Chem. 278・2

      Pages: 1310-1315

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] TRANSLOCATION OF ANALOGUES OF THE ANTIMICROBIAL PEPTIDES MAGAININ AND BUFORIN ACROSS HUMAN CELL MEMBRANES2003

    • Author(s)
      K.TAKESHIMA et al.
    • Journal Title

      J.BIOL.CHEM. 278-2

      Pages: 1310-1315

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Position-dependent hydrophobicity of the antimicrobial magainin peptide affects on the mode of peptide-lipid interactions and selective toxicity2002

    • Author(s)
      T.Tachi et al.
    • Journal Title

      Biochemistry 41・34

      Pages: 10723-10731

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] POSITION-DEPENDENT HYDROPHOBICITY OF THE ANTIMICROBIAL MAGAININ PEPTIDE AFFECTS ON THE MODE OF PEPTIDE-LIPID INTERACTIONS AND SELECTIVE TOXICITY2002

    • Author(s)
      T.TACHI et al.
    • Journal Title

      BIOCHEMISTRY 41-34

      Pages: 10723-10731

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Publications] Kenta Takshima et al.: "Translocation of Analogues of the Antimicrobial Peptides Magainin and Buforin across Human Cell Membranes"J. Biol. Chem.. 278・2. 1310-1315 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Tomoya Tachi et al.: "Position-Dependent Hydrophobicity of the Antimicrobial Magainin Peptide Affects on the Mode of Peptide-Lipid Interactions and Selective Toxicity"Biochemistry. 41・34. 10723-10731 (2002)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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