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Studies on the elucidantion of action mechanisms of tachyplesin analogs as anti-HIV peptides

Research Project

Project/Area Number 05671871
Research Category

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

Allocation TypeSingle-year Grants
Research Field 医薬分子機能学
Research InstitutionKYOTO UNIVERSITY

Principal Investigator

FUJII Nobutaka  Kyoto Univ., Fac.Pharm.Sci., Professor, 薬学部, 教授 (60109014)

Co-Investigator(Kenkyū-buntansha) TAMAMURA Hirokazu  Kyoto Univ., Fac.Pharm.Sci., Assistant Professor, 薬学部, 助手 (80217182)
Project Period (FY) 1993 – 1994
Project Status Completed (Fiscal Year 1994)
Budget Amount *help
¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1994: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1993: ¥1,300,000 (Direct Cost: ¥1,300,000)
Keywordsanti-HIV activity / tachyplesin / polyphemusin / T22 / beta-sheet / T cell / AgOTf-DMSO / HCI / solution-phase synthesis / AgOTf / DMSO / NMR / β-sheet
Research Abstract

We found a novel anti-HIV peptide, T22, through a structure-activity relationship study on horseshoe crab antimicrobial peptides, tachyplesin and polyphemusin. In order to elucidate the action mechanisms of T22, and to develop new anti-HIV agents based on T22, we carried out the following investigations.
1.Conformatinal analysis of T22
The secondary structure of T22 was confirmed to be similar to that of tachyplesin I using NMR.The antiparallel beta-sheet structure and the several amino acid chains of the beta-sheet plane of T22 are though to be associated with the expression of anti-HIV activity.
2.Action mode of T22
We investigated molecular paramenters necessary for the expression of the strong anti-HIV activity of T22. The results suggest that the anti-HIV activity of T22 is mediated through the interaction with chiral component (s) of the cell or virus, and that there is a positive correlation between cytotoxicity and membrane permeability. Furthermore we found that T22 binds to T cel … More l surfaces, and that there is a positive correlation between binding activity and anti-HIV activity. In addition, a binding site on the T22 peptide was idetified.
3.Solution-phase synthesis of T22
The synthetic method of T22 on a large scale using solution-phase techniques was established in order to provide sufficient materials for mechanical and preclinical studies.
4.Development of a regioselective disulfide bond-forming method
A regioselective disulfide bond-forming method using the AgOTf-DMSO/HCl system was developed in order to facilitate the unambiguous synthesis of the two-disulfide and Trp containing peptides, such as T22 analogs.
5.Structure-activity relationshipt of T22
Using the above regioselective disulfide bond-forming method, several T22 analogs were synthesized and provided for the structure-activity relationship study in order to define the active site and cytotoxic site of T22.
These findings will lead to the development of new types of anti-AIDS drugs with novel mechanisms of action. Less

Report

(3 results)
  • 1994 Annual Research Report   Final Research Report Summary
  • 1993 Annual Research Report
  • Research Products

    (26 results)

All Other

All Publications (26 results)

  • [Publications] H.Tamamura et al.: "Antimicrobial Activity and Conformation of Tachyplesin I and Its Analogs" Chem.Pharm.Bull.41. 978-980 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] H.Tamamura et al.: "A Comparative Study of the Solution Structure of Tachyplesin I and a Novel Anti‐HIV Synthetic Peptide,T22(Tyr^<5,12>,Lys^7]‐Polyphemusin II),Determined by Nuclear Magnetic Resonance" Biochem.Biophys.Acta. 1163. 209-216 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] H.Tamamura et al.: "Disulfide Bond Formation in S‐Acetamidomethyl Cysteine‐Containing Peptides by the Combination of Silver Trifluoromethanesulfonate and Dimethylsulfoxide/Aqueous HCI" Tetrahedron Lett.34. 4931-4934 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] A.Otaka et al.: "Molecular Parameters for the Anti‐Human Immunodeficiency Virus Activity of T22([Tyr^<5,12>,Lys^7]‐Polyphemusin II)" Biol.Pharm.Bull.17. 1669-1672 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] B.S.Weeks et al.: "Lymphocytes and Promonocytes Attach to the Synthetic[Tyr^<5,12>,Lys^7]‐Polyphemusin II Peptide" Biochem.Biophys.Res.Commun.202. 470-475 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] H.Tamamura et al.: "Structure‐Activity Relationships of an Anti‐HIV Peptide,T22" Biochem.Biophys.Res.Commun.205. 1729-1735 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] H.Tamamura et al.: "Anti‐HIV Activity and Conformational Analysis of a Novel Synthetic Peptide,T22([Tyr^<5,12>,Lys^7]‐Polyphemusin II)" Peptides. 1994. 455-458 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] H.Tamamura et al.: "Solution‐Phase Synthesis of an Anti‐Human Immunodeficiency Virus Peptide,T22([Tyr^<5,12>,Lys^7]‐Polyphemusin II),and the Modification of Trp by the ρ‐Methoxybenzyl Group of Cys during Trimethylsilyl Trifluoromethanesulfonate Deprotcction" Chem.Pharm.Bull.43. 12-18 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] H.Tamamura et al.: "Disulfide bond‐forming reaction using dimethylsulfoxide/aqueous HCl system and its application to regioselective two disulfide bond formation" Int.J.Peptide Protein Res.45. 312-319 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] H.Tamamura et al.: "Antimicrobial Activity and Conformation of Tachyplesin I and Its Analogs" Chem.Pharm.Bull.41. 978-980 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] H.Tamamura et al.: "A Comparative Study of the Solution Structure of Tachyplesin I and a Novel Anti-HIV Synthetic Peptide, T22 ( Tyr^<5,12>, Lys^7] -Polyphemusin II) , Detarmined by Nuclear Magnetic Resonance" Biochim.Biophys.Acta. 1163. 209-216 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] H.Tamamura et al.: "Disulfide Bond Formation in S-Acetamidomethyl Cysteine-Containing Peptides by the Combination of Silver Trifluoromethanesulfonate and Dimethylsulfoxide/Aqueous HCl" Tetrahedron Lett.34. 4931-4934 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] A.Otaka et al.: "Molecular Paramenters for the Anti-Human Immunodeficiency Virus Activity of T22 ( [Tyr^<5,12>, Lys^7] -Polyphemusin II)" Biol.Pharm.Bull.17. 1669-1672 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] B.S.Weeks et al.: "Lymphocytes and Promonocytes Attach to the Synthetic [Tyr^<5,12>, Lys^7] -Polyphemusin II Peptide" Biochem.Biophys.Res.Commun.202. 470-475 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] H.Tamamura et al.: "Structure-Activity Relationships of an Anti-HIV Peptide, T22" Biochem.Biophys.Res.Commun.205. 1729-1735 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] H.Tamamura et al.: "Anti-HIV Activity and Conformational Analysis of a Novel Synthetic Peptide, T22 ( [Tyr^<5,12>, Lys^7] -Polyphemusin II)" Peptides. 455-458 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] H.Tamamura et al.: "Solution-Phase Synthesis of an Anti-Human Immunodeficiency Virus Peptide, T22 ( [Tyr^<5,12>, Lys^7] -Polyphemusin II) , and the Modification of Trp by the p-Methoxybenzyl Group of Cys during Trimethylsilyl Trifluoromethanesulfonate Deprotection" Chem.Pharm.Bull.43. 12-18 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] H.Tamamura et al.: "Disulfide bond-forming reaction using dimethylsulfoxide/aqueous HCI system and its application to regioselective two disulfide bond formation" Int.J.Peptide Protein Res.45. 312-319 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] A.Otaka et al.: "Molecular Parameters for the Anti-Human Immunodeficiency Virus Activity of T22([Tyr^<5,12>,Lys^7]-Polyphemusin II)" Biol.Pharm.Bull.17. 1669-1672 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] B.S.Weeks et al.: "Lymphocytes and Promonocytes Attach to the Synthetic [Tyr^<5,12>,Lys^7]-Polyphemusin II Peptide" Biochem.Biophys.Res.Commun.202. 470-475 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] H.Tamamura et al.: "Structure-Activity Relationships of an Anti-HIV Peptide,T22" Biochem.Biophys.Res.Commun.205. 1729-1735 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] H.Tamamura et al.: "Anti-HIV Activity and Conformational Analysis of a Novel Synthetic Peptide,T22([Tyr^<5,12>,Lys^7]-Polyphemusin II)" Peptides. 1994. 455-458 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] H.Tamamura et al.: "Solution-Phase Synthesis of an Anti-Human Immunodeficiency Virus Peptide,T22([Tyr^<5,12>,Lys^7]-Polyphemusin II),and the Modification of Trp by the p-Methoxybenzyl Group of Cys during Trimethylsilyl Trifluoromethanesulfonate Deprotection" Chem.Pharm.Bull.43. 12-18 (1995)

    • Related Report
      1994 Annual Research Report
  • [Publications] H.Tamamura et al.: "Disulfide bond-forming reaction using dimethylsulfoxide/aqueous HCl system and its application to regioselective two disulfide bond formation" Int.J.Peptide Protein Res.45. 312-319 (1995)

    • Related Report
      1994 Annual Research Report
  • [Publications] H.Tamamura,M.Kuroda,M.Masuda,A.Otaka,S.Funakoshi,H.Nakashima,N.Yamamoto,M.Waki,A.Matsumoto,J.M.Lancelin,D.Kohda,S.Tate,F.Inagaki,N.Fujii: "A comparative study of solution structures of tachyplesin I and a novel anti-HIV synthetic peptide,T22([Tyr5,12,Lys7]-polyphemusin II),determined by nuclear magnetic resonance" Biochim.Biophys.Acta. 1163. 209-216 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] H.Tamamura,R.Ikoma,M.Niwa,S.Funakoshi,T.Murakami,N.Fujii: "Antimicrobial activity and conformation of tachyplesin I and its analogs" Chem.Pharm.Bull.41. 978-980 (1993)

    • Related Report
      1993 Annual Research Report

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Published: 1993-04-01   Modified: 2016-04-21  

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