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Development of fine micro analytical method of drug recognition function of sugar chains

Research Project

Project/Area Number 11307054
Research Category

Grant-in-Aid for Scientific Research (A).

Allocation TypeSingle-year Grants
Section一般
Research Field Physical pharmacy
Research InstitutionKYOTO UNIVERSITY

Principal Investigator

NAKAGAWA Terumichi  Kyoto University, Graduate School of Pharmaceutical Sciences, Professor, 薬学研究科, 教授 (70025708)

Co-Investigator(Kenkyū-buntansha) SHIBUKAWA Akimasa  Kyoto University, Graduate School of Pharmaceutical Sciences, Associate Professor, 薬学研究科, 助教授 (30170913)
KURODA Yoshihiro  Kyoto University, Graduate School of Pharmaceutical Sciences, Associate Professor, 薬学研究科, 助教授 (90093236)
Project Period (FY) 1999 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥40,700,000 (Direct Cost: ¥40,700,000)
Fiscal Year 2000: ¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 1999: ¥37,400,000 (Direct Cost: ¥37,400,000)
Keywordsglycochain / plasma protein binding / microheterogeneity / high-performance frontal analysis / ESI-T0F-MS / sodium channel inactivation gate peptide / prion protein / capillary electrophoresis
Research Abstract

A novel analytical system using capillary electrophoresis (CE) and mass spectroscopy (MS) was developed to investigate the structural effect of glycoproteins upon drug binding affinity. α1-acid glycoprotein (AGP) was used as a model glycoprotein, and the binding affinities of AGP glycoforms and genetic variants to model basic drugs were evaluated.
(a) The biantennary glycochains which locate only near the drug binding site on AGP molecule does not give any significant effect upon the enantioselective binding of AGP to model basic drugs (disopyramide and verapamil).
(b) AGP has three major genetic variants, A-variant, F1-variant and S-variant. A-variant shows higher enantioselectivity in the binding with the enantiomers of model drugs than F1^*S variants, while these genetic variants show almost the same enantioselectivity in the binding to verapamil enantiomers.
(c) CE/MS system using sheathless ESI method allows one-order higher detectability in the analyses of tryptic digests of AGP var … More iants than conventional CE method using UV detection.
In order to investigate the effect of microheterogeneity of glycoproteins upon the function and the secondary structure of the proteins, the structural chemistry of several synthesized peptide fragments of Na-channel protein and prion protein were studied by using NMR, molecular orbital method and CE spectroscopy. The synthesized fragments correspond to the major peptide portion responsible for the secondary structure and/or the function of the proteins. The followings were found.
(a) The secondary structure of model peptide fragments changes depending on the hydrophobicity of environment due to the nature and the component of solvents.
(b) Glycans containing both hydrophobic moiety and hydrophobic moiety create local hydrophobic space with different micro-permittivity depending on nature, sequence and the branching structure of glycans. It is suggested that the creation of hydrophobic local environment would cause the change of secondary structure of protein, resulting in the regulation of function and amyloid fibril formation. Less

Report

(3 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • Research Products

    (27 results)

All Other

All Publications (27 results)

  • [Publications] Yukihiro Kuroda et al: "Role of Biantennary Glycans and Genetic Variants of Human α_1-Acid Glyooprotein in Enantioselective Binding of Basic Drugs as Studied by High Performance Frontal Analysis /Capillary Electrophoresis"Pharm.Res.. (印刷中).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Akimasa Shibukawa et al.: "Plasma protein binding study of oxybutynin by high-performance frontal analysis"J.Chromatogr.B. (印刷中).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Akimasa Shibukawa et al.: "Binding study of desethyloxybutynin using high-performance frontal analysis method"J.Chromatogr.B. (印刷中).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Yukihiro Kuroda et al.: "Structural study of the sodium channel inactivation gate peptide including an isoleucine-phenylalanine-methionine motif and its analogous peptide (phenylalanine/glutamine) in trifluoroethanol solution and SDS micelles"J.Peptide Res.. 56・3. 172-184 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Yukihiro Kuroda et al.: "Interactions between local anesthetics and Na^+-channel inactivation gate peptides in phosphatidylserine liposomes as studied by ^1H-NMR spectroscopy"Chem.Pharm.Bull.. 48・9. 1293-1298 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Yukihiro Kuroda et al.: "Orientations and locations of local anesthetics benzocaine and butamben in phospholipid membranes as studied by 2H NMR spectroscopy"J.Membr.Biol.. 177・2. 117-128 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Yukihiro Kuroda et al.: "Oligopeptide-mediated stabilization of the α-helix of a prion protein peptide"J.Am.Chem.Soc.. 122. 12596-12597 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kazuhide Miyamoto et al.: "Solution structures of the inactivation gate particle peptides of rat brain type-IIA and human heart sodium channels in SDS micelles"J.Peptide Res.. 57. (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Yukihiro Kuroda et al.: "Role of Biantennary Glycans and Genetic Variants of Human α_1-Acid Glycoprotein in Enantioselective Binding of Basic Drugs as Studied by High Performance Frontal Analysis/Capillary Electrophoresis"Pharm.Res.. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Akimasa Shibukawa et al.: "Plasma protein binding study of oxybutynin by high-performance frontal analysis"J.Chromatogr.B. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Akimasa Shibukawa et al.: "Binding study of desethyloxybutynin using high-performance frontal analysis method"J.Chromatogr.B. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Yukihiro Kuroda et al.: "Structural study of the sodium channel inactivation gate peptide including an isoleucine-phenylalanine-methionine motif and its analogous peptide (phenylalanine/glutamine) in trifluoroethanol solution and SDS micelles"J.Peptide Res.. 56-3. 172-184 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Yukihiro Kuroda et al.: "Interactions between local anesthetics and Na^+-channel inactivation gate peptides in phosphatidylserine iposomes as studied by ^1H-NMR spectroscopy"Chem.Pharm.Bull.. 48-9. 1293-1298 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Yukihiro Kuroda et al.: "Orientations and locations of local anesthetics benzocaine and butamben in phospholipid membranes as studied by 2H NMR spectroscopy"J.Membr.Biol.. 177-2. 117-128 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Yukihiro Kuroda et al.: "Oligopeptide-mediated stabilization of the α-helix of a prion protein peptide"J.Am.Chem.Soc.. 122. 12596-12597 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kazuhide Miyamoto et al.: "Solution structures of the inactivation gate particle peptides of rat brain type-ILA and human heart sodium channels in SDS micelles"J.Peptide Res.. 57 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Yukihiro Kuroda et al.: "Role of Biantennary Glycans and Genetic Variants of Human α_1-Acid Glycoprotein in Enantioselective Binding of Basic Drugs as Studied by High Performance Frontal Analysis/Capillary Electrophoresis"Pharm.Res.. (印刷中).

    • Related Report
      2000 Annual Research Report
  • [Publications] Akimasa Shibukawa et al.: "Plasma protein binding study of oxybutynin by high-performance frontal analysis"J.Chromatogr.B. (印刷中).

    • Related Report
      2000 Annual Research Report
  • [Publications] Akimasa Shibukawa et al.: "Binding study of desethyloxybutynin using high-performance frontal analysis method"J.Chromatogr.B. (印刷中).

    • Related Report
      2000 Annual Research Report
  • [Publications] Yukihiro Kuroda et al.: "Structural study of the sodium channel inactivation gate peptide including an isoleucine-phenylalanine-methionine motif and its analogous peptide (phenylalanine/glutamine) in trifluoroethanol solution and SDS micelles"J.Peptide Res.. 56・3. 172-184 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Yukihiro Kuroda et al.: "Interactions between local anesthetics and Na^+-channel inactivation gate peptides in phosphatidylserine liposomes as studied by ^1H-NMR spectroscopy"Chem.Pharm.Bull.. 48・9. 1293-1298 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Yukihiro Kuroda et al.: "Orientations and locations of local anesthetics benzocaine and butamben in phospholipid membranes as studied by 2H NMR spectroscopy"J.Membr.Biol.. 177・2. 117-128 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Yukihiro Kuroda et al.: "Oligopeptide-mediated stabilization of the α-helix of a prion protein peptide"J.Am.Chem.Soc.. 122. 12596-12597 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kazuhide Miyamoto et al.: "Solution structures of the inactivation gate particle peptides of rat brain type-IIA and human heart sodium channcls in SDS micelles"J.Peptide Res.. 57. (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Yukihiro Kuroda: "The Role of Branching Glycan of Human α_1-Acid Glycoprotein in Enantioselective Binding to Basic Drugs as Studied by Capillary Electrophoresis"Analytical Biochemistry. 268. 9-14 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Maria Esther Rodrigues Rosas: "Binding Study of Semotiadil and Levosemotiadil with α1-Acid Glycoprotein Usiug High-Performance Frontal Analysis"Analytical Biochemistry. 274. 27-33 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Akimasa Shibukawa: "Development of high-performance frontal analysis and the application to the study of drug-plasma protein binding"Trends in Analytical Chemistry. 18・8. 549-556 (1999)

    • Related Report
      1999 Annual Research Report

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Published: 1999-04-01   Modified: 2016-04-21  

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