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Design and Synthesis of Novel Inhibitors Modeled on Plant Protease Inhibitors

Research Project

Project/Area Number 63470023
Research Category

Grant-in-Aid for General Scientific Research (B)

Allocation TypeSingle-year Grants
Research Field 天然物有機化学
Research InstitutionKyushu University

Principal Investigator

WAKI Michinori  Kyushu University, Faculty of Science, Research Associate, 理学部, 助手 (30037212)

Co-Investigator(Kenkyū-buntansha) AOYAGI Haruhiko  Kyushu University, Faculty of Science, Associate Professor, 理学部, 助教授 (80037267)
OHNO Motonori  Kyushu University, Faculty of Science, Professor, 理学部, 教授 (30038434)
Project Period (FY) 1988 – 1989
Project Status Completed (Fiscal Year 1989)
Budget Amount *help
¥4,200,000 (Direct Cost: ¥4,200,000)
Fiscal Year 1989: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 1988: ¥2,600,000 (Direct Cost: ¥2,600,000)
KeywordsProtease inhibitor / Plant inhibitor / Trypsin inhibitory peptide / Chymotrypsin inhibitory peptide / Peptide synthesis / トリプシン阻害ペプチド / プロテアーゼインヒビター / 植物起源インヒビター
Research Abstract

To search and develop a novel potent protease inhibitor, a reactive-site peptide of soybean Bowman-Birk inhibitor (BBI) with dual inhibitory activities against trypsin (Tsin) and chymotrypsin (Csin) was selected as structural bases. 1. Reactive-site peptides of BBI: A parent nonapeptide of the anti-Tsin domain of BBI, in which the P_1 site is Lys for Tsin inhibitor (la) or Tyr for Csin inhibitor (1b), and the nonapeptide analog (2a or 2b) of 1, in which the scissile reactive-site dipeptide is replaced by uncleavable statine-type isostere (3a or 3b) derived from Lys or Tyr, were devised as synthetic targets. (1) Isosteres: Effective synthetic route for diastereomeric 3 from L-amino acid was established. (2) Tsin or Csin inhibition: Only one diastereomer (3S,4S)-3a or (3S,4S)-2b inhibited Tsin or Csin weakly, indicating that the specific stereochemistry of the isosteric residue is required for the activity-exhibition. By contrast, the parent 1b was the most potent Csin-inhibitor (Ki=1.2 x 10^<-7> M) among the BBI-related synthetic peptides. 2. Reactive-site peptides of peanut inhibitor B-III: BBI-type nonapeptide (4) and B-III-type undecapeptide (5) with the reactive-site of B-III were synthesized. 5 inhibited both Tsin and Csin, while 4 only Tsin, indicating that the undecapeptide-structure of 5 is a minimum constituent to exhibit the B-III activity. 3. Csin-inhibitory dipeptides: A series of dipeptides with sterically constrained dehydro or methanophenylalanine and related simple dipeptides were designed and synthesized. Evaluation of the inhibitory activities and conformational analysis suggest the backbone structure of the Csin- inhibitory dipeptides to be in a specific inhibitory conformation. Such structure may become an important unit in designing of more effective inhibitors.

Report

(3 results)
  • 1989 Annual Research Report   Final Research Report Summary
  • 1988 Annual Research Report
  • Research Products

    (20 results)

All Other

All Publications (20 results)

  • [Publications] Tomohisa OGAWA: "Enzyme inhibition by dipeptides containing 2,3-methanophenylalanine,a sterically constrained amino acid" FEBS Lett. 250. 227-230 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Yasuyuki SHIMOHIGASHI: "Specific inhibitory conformation of dipeptides for chymotrypsin" Biochem Biophys.Res.Commun 印刷中. (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Tomohisa OGAWA: "Enzyme-inhibitory conformation of dipeptides containing sterically constrained amino acid 2,3:methanophenylalanine" Peptide Res 印刷中. (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Hiroshi SAKAMOTO: "H-D-Leu-Phe-OBZl inhibits chymotrypsin with specific conformation similar to that of H-D-PHe-Leu-OMe" FEBS Lett 投稿中. (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Yasuyuki SHIMOHIGASHI: "Design and synthesis of dipeptide inhibitors directed to chymotrypsin catalytic center with specific inhibitory conformation" J.Mol.Recogn 投稿中. (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Makoto SHIOTA: "Functional conversion of an anti-trypsin domain peptide of Bowman-Birk inhibitor into an anti-chymotrypsin peptide" FEBS Lett 投稿中. (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Tomohisa Ogawa: "Enzyme inhibition by dipeptides containing 2, 3-methanophenylalanine, a sterically constrained amino acid" FEBS Lett., 250-2, 227-230, 1989.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Yasuyuki Shimohigashi: "Specific inhibitory conformation of dipeptides for chymotrypsin" Biochem.Biophys.Res.Commun. 1990.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Tomohisa Ogawa: "Enzyme-inhibitory conformation of dipeptides containing sterically constrained amino acid 2, 3-methanophenylalanine" Peptide Res., 1990.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Hiroshi Sakamoto: "H-D-Leu-Phe-OBzl inhibits chymotrypsin with specific conformation similar to that of H-D-Phe-Leu-OMe" FEBS Lett., 1990.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Yasuyuki Shimohigashi: "Design and synthesis of dipeptide inhibitors directed to chymotrypsin catalytic center with specific inhibitory conformation" J. Mol. Recogn., 1990.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Makoto Shiota: "Functional conversion of an anti-trypsin domain peptide of Bowman-Birk inhibitor into an anti-chymotrypsin peptide" FEBS Lett., 1990.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Tomohisa OGAWA: "Enzyme inhibition by dipeptides containing 2,3-methanophenylalanine,a sterically constrained amino acid" FEBS Lett.250. 227-230 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Yasuyuki SHIMOHIGASHI: "Specific inhibitory conformation of dipeptides for chymotrypsin" Biochem.Biophys.Res.Commun.(1990)

    • Related Report
      1989 Annual Research Report
  • [Publications] Tomohisa OGAWA: "Enzyme-inhibitory conformation of dipeptides containing sterically constrained amino and 2,3-methanophenylalanine" Peptide Res.(1990)

    • Related Report
      1989 Annual Research Report
  • [Publications] Hiroshi SAKAMOTO: "H-D-Leu-Phe-OB_2l inhibits chymotrypsin with specific conformation similar to that of H-D-Phe-Leu-OMe" FEBS Lett.(1990)

    • Related Report
      1989 Annual Research Report
  • [Publications] Yasuyuki SHIMOHIGASHI: "Design and synthesis of dipeptide inhibitors directed to chymotrypsin catalytic center with specific inhibitory conformation" J.Mol.Recogn.(1990)

    • Related Report
      1989 Annual Research Report
  • [Publications] Makoto SHIOTA: "Functional conversion of an anti-trypsin domain peptide of Bowman-Birk inhibitor into an anti-chymotripsin peptide" FEBS Lett.(1990)

    • Related Report
      1989 Annual Research Report
  • [Publications] 小川智久: 生化学. 60. 811-811 (1988)

    • Related Report
      1988 Annual Research Report
  • [Publications] Tomohisa OGAWA: Peptide Chemistry 1988. (1989)

    • Related Report
      1988 Annual Research Report

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Published: 1988-04-01   Modified: 2016-04-21  

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