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Studies on the molecular mechanism of thrombin receptor activation by means of ligand peptides containing a series of fluorinated phenylalanines

Research Project

Project/Area Number 08458178
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Bioorganic chemistry
Research InstitutionKYUSHU UNIVERSITY

Principal Investigator

SHIMOHIGASHI Yasuyuki  Kyushu University・Faculty of Science Professor, 理学部, 教授 (00211293)

Co-Investigator(Kenkyū-buntansha) NOSE Takeru  Kyusu University・Faculty of Science, Reseach Associate, 理学部, 助手
Project Period (FY) 1996 – 1997
Project Status Completed (Fiscal Year 1997)
Budget Amount *help
¥6,300,000 (Direct Cost: ¥6,300,000)
Fiscal Year 1997: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 1996: ¥4,800,000 (Direct Cost: ¥4,800,000)
KeywordsThrombin receptor / Receptor activation / Tethered-ligand / Fluoroamino acids / Fluorophenylalanines / Platelet aggregation / Thrombosis
Research Abstract

The receptor of serine protease thrombin is a novel type of receptor, in which the peptite ligand is present in the N-terminal portion of the receptor itself. It was found that the receptor can be activated by the synthetic peptide Ser-Phe-Leu-Leu-Arg-Asn-Pro (SFLLRNP) without thrombin, and that Phe-2 of this peptide is crucially important to the receptor. recognition and activation. The aim of the present study is to clarify the interaction mode between Phe-2-phenyl and thrombin receptor aromatic groups. There are two possibilities for interaction of the ligand Phe-phenyl group : i.e., pi-pi stacking interaction and CH/pi interaction. To differentiate these interactions, we have incorporated a series of fluorinated phenylalanines. Fluorine is the most electronegative atom, the size of which is almost the same as hydrogen. It was immediately recognized that the fluorine substitution is allowed ony at the para-position. The derivative with pentafluorophenylalanine was totally devoid of … More activity. These results suggested that Phe-2 requires hydrogen atom(s) on the benzene ring presumably for interaction with the receptor. No activity enhancement observed for analogs with para-chloro-, bromo-, or iodophenylalanine indicated the importance of a high electronegativity of fluorine to intensify a dipole of CH(s) remaining in the Phe-2-benzenering, and suggested the presence of face-to-edge pi-pi interaction. Reduced but full activation by the derivative of 3,4,5-trifluorophenylalanine marked a hydrogen at position 6 as a structural element for direct interaction with the receptor aromatic ring. When strongly meta-orienting the trifluoromethyl group was introduced, only the derivative of 3-trifluoromethylpehnylalanine was fully active. All these results indicated that hydrogens at position 5 and 6 are the most important structural element for receptor interaction and that the interaction of Phe-2 of SFLLRNP appeared to be a face-to-edge pi-pi interaction based upon the CH/pi interaction between the Phe-2-phenyl group and the receptor aromatic group. Less

Report

(3 results)
  • 1997 Annual Research Report   Final Research Report Summary
  • 1996 Annual Research Report
  • Research Products

    (29 results)

All Other

All Publications (29 results)

  • [Publications] Yasuyuki Shimohigashi: "Human Thrombin Receptors are Insensitive to Thrombin-like Snake Venom Enzymes" Biochem.Mol.Biol.Int.35・2. 415-421 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Takeru Nose: "Structural Requirements of Leu-4 and Arg-5 Residues of Thrombin Receptor-tethered Ligand Peptide for Receptor Activation" Peptide Chemistry 1994. 365-368 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Yasuyuki Shimohigashi: "π-π Interaction between Tethered-ligand Peptide and its Binding Site in Receptor Activation" Peptide Chemistry 1994. 369-372 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Takeru Nose: "Different Roles of Two Consecutive Leucine Residues in Receptor-Tethered Ligand Peptide(SFLLRNP)in Thrombin Receptor Activation" Bull.Chem.Soc.Jpn.68・9. 2695-2698 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Takeru Nose: "Functional Roles of Phenylalanine -2 of Thrombin Receptor-Tethered Ligand Peptide in Platelet Activation" Peptide Chemistry 1995. 265-268 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Tsugumi Fujita: "A Molecular Design of the Thrombin Receptor Antagonist" Peptide Chemistry 1995. 261-264 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Takeru Nose: "Platelet Aggregation Activity of Thrombin Receptor-Tethered Peptide Ligand Containing Free Thiol or Activated SH Group" Peptide Chemistry 1996. 277-280 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Tsugumi Fujita: "Design and Synthesis of Para-Fluorophenylalanine Amide Derivatives Containing N-Terminal Thiol as Thrombin Receptor Antagonist" Peptide Chemistry 1996. 233-236 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Tsugumi Fujita: "Agonist-Antagonist Structure-Activity Relationships of Thrombin Receptor Tethered Ligand Peptide" Peptide Science 1997. (印刷中). (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Takeru Nose: "The Role of Arginine in Thrombin Receptor Tethered-Ligand Peptide in Intramolecular Receptor Binding and Self -activation" Bull.Chem.Soc.Jpn.(印刷中). (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Yasuyuki Shimohigashi: "Human Thrombin Receptors are Insensitive to Thrombin-like Snake Venom Enzymes" Biochem.Mol.Biol.Int. 35(2). 415-421 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Takeru Nose: "Structural Requirements of Leu-4 and Arg-5 Residues of Thrombin Receptor-tethered Ligand Peptide for Receptor Activation" Peptide Chemistry 1994. 365-368 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Yasuyuki Shimohigashi: "pi-pi Interaction between Tethered-ligand Peptide and its Binding Site in Receptor Activation" Peptide Chemistry 1994. 369-372 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Takeru Nose: "Different Roles of Two Consecutive Leucine Residues in Receptor-Tethered Ligand Peptide (SFLLRNP) in Thrombin Receptor Activation" Bull. Chem. Soc. Jpn.68(9). 2695-2698 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Takeru Nose: "Functional Roles of Phenylalanine-2 of Thrombin Receptor-Tethered Ligand Peptide in Platelet Activation" Peptide Chemistry 1995. 265-268 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Tsugumi Fujita: "A Molecular Design of the Thrombin Receptor Antagonist" Peptide Chemistry 1995. 261-264 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Takeru Nose: "Platelet Aggregation Activity of Thrombin Receptor-Tethered Peptide Ligand Containing Free Thiol or Activated SH Group" Peptide Chemistry 1996. 277-280 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Tsugumi Fujita: "Design and Synthesis of para-Fluorophenylalanine Amide Derivatives Containing N-Terminal Thiol as Thrombin Receptor Antagonist" Peptide Chemistry 1996. 233-236 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Tsugumi Fujita: "Agonist-antagoniststructure-activity relationships of thrombin receptor tethered ligand reptide" Peptide Science 1997. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Takeru Nose: "The Role of Arginine in Thrombin Receptor Tethered-Ligand Peptide in Intramolecular Receptor Binding and Self-activation" Bull.Chem.Soc.Jpn.(in press). (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Takeru Nose: "The Role of Arginine in Thrombin Receptor Tetherd-Ligand Peptide in Intramolecular Receptor Binding and Self-activation" Bull.Chem.Soc.Jpn.(印刷中). (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] Tsugumi Fujita: "Agonist-antagonist Structure-activity Relationships of Thrombin Receptor Tethered Ligand Peptide" Peptide Science 1997. (印刷中). (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] Tsugumi Fujita: "Design and Synthesis of para-Fluorophenylalanine Amide Derivatives Containing N-Terminal Thiol as Thrombin Receptor Antagonist" Peptide Chemistry 1996. 233-236 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Takeru Nose: "Platelet Aggregation Activity of Thrombin Receptor-Tetherd Peptide Ligand Containing Free Thiol or Activated SH Group" Peptide Chemistry 1996. 277-280 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Takeru Nose: "Platelet Aggregation Activity of Thrombin Receptor-Tothered Peptide Ligand Containing Free Thiol or Activated SH Group" Peptide Chemistry 1996. (印刷中).

    • Related Report
      1996 Annual Research Report
  • [Publications] Tsugumi Fujita: "Design and Synthesis of para-Fluorophenylalanine Amide Derivatives Containing N-Terminal Thiol as Thromibin Receptor Ancagonist" Peptide Chemistry 1996. (印刷中).

    • Related Report
      1996 Annual Research Report
  • [Publications] Takeru Nose: "Functional Roles of Phenylalanine-2 of Thrombin Receptor Tethered Ligand Peptide in Platelet Activation" Peptide Chemistry 1995. 265-268 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Tsugumi Fujita: "A Moleular Design of Thrombin Receptor Ancagonist" Peptide Chemistry 1995. 261-264 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Takeru Nose: "Differential Roles Two Conseartive Phenylalaine Residues in Thrombin Receptor Tethered Ligand Peptide in Thrombin Receptor Activation" Bull.Chem.Soc. Jpn.68・9. 2695-2698 (1995)

    • Related Report
      1996 Annual Research Report

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Published: 1996-04-01   Modified: 2016-04-21  

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