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Development of mid-size drugs based on peptidomimetic

Research Project

Project/Area Number 15H04652
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Drug development chemistry
Research InstitutionTokyo Medical and Dental University

Principal Investigator

TAMAMURA Hirokazu  東京医科歯科大学, 生体材料工学研究所, 教授 (80217182)

Co-Investigator(Kenkyū-buntansha) 野村 渉  東京医科歯科大学, 生体材料工学研究所, 准教授 (80463909)
水口 貴章  東京医科歯科大学, 生体材料工学研究所, 助教 (30732557)
大橋 南美  東京医科歯科大学, 生体材料工学研究所, 助教 (90707051)
Research Collaborator YOSHIMURA Kazuhisa  
MURAKAMI Tsutomu  
Project Period (FY) 2015-04-01 – 2018-03-31
Project Status Completed (Fiscal Year 2017)
Budget Amount *help
¥17,030,000 (Direct Cost: ¥13,100,000、Indirect Cost: ¥3,930,000)
Fiscal Year 2017: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2016: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2015: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000)
Keywords中分子 / ペプチドミメティック / 環状ペプチド / HIV / がん / ステープルペプチド / CXCR4 / GPCR / ヒト免疫不全ウイルス / 医薬品開発 / 中分子創薬 / 二次構造 / 2価型 / 二量体 / 高次構造模倣型 / 2価結合型GPCRリガンド
Outline of Final Research Achievements

Peptidomimetics that mimic conformation such as secondary and tertiary structures of peptides/proteins have led to the recent development of anti-cancer and anti-HIV agents. Some examples are described as follows. Chemokine receptor CXCR4 antagonists based on cyclic peptides having conformationally constrained structures have been synthesized as agents with anti-chemotactic activity against cancer cells and inhibitory activity against HIV entry. HIV protein-derived stapled peptides with helix mimetics have been developed as HIV integrase inhibitors. Dimer and trimer mimetics of a C-terminal helical region (CHR/C34) of an envelope protein gp41 have been developed as HIV fusion inhibitors. In addition, bivalent ligands based on the above CXCR4 antagonists such as 14-mer peptide T140 derivatives have been synthesized to produce effective metastatic inhibition with the therapeutic potential. Taken together, these advantaged of mid-size drugs were shown.

Report

(4 results)
  • 2017 Annual Research Report   Final Research Report ( PDF )
  • 2016 Annual Research Report
  • 2015 Annual Research Report
  • Research Products

    (26 results)

All 2018 2017 2016 2015

All Journal Article (12 results) (of which Int'l Joint Research: 6 results,  Peer Reviewed: 12 results,  Open Access: 12 results,  Acknowledgement Compliant: 4 results) Presentation (12 results) (of which Int'l Joint Research: 10 results,  Invited: 7 results) Book (2 results)

  • [Journal Article] Synthesis of a Chloroalkene Dipeptide Isostere-Containing Peptidomimetic and Its Biological Application2018

    • Author(s)
      Takuya Kobayakawa, Yudai Matsuzaki, Kentaro Hozumi, Wataru Nomura, Motoyoshi Nomizu, Hirokazu Tamamura
    • Journal Title

      ACS Med. Chem. Lett.

      Volume: 9 Issue: 1 Pages: 6-10

    • DOI

      10.1021/acsmedchemlett.7b00234

    • Related Report
      2017 Annual Research Report 2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Bivalent 14-mer Peptide Ligands of CXCR4 with Polyproline Linkers with Anti-Chemotactic Activity against Jurkat Cells2017

    • Author(s)
      Tomohiro Tanaka, Toru Aoki, Wataru Nomura, Hirokazu Tamamura
    • Journal Title

      J. Pept. Sci.

      Volume: 印刷中 Issue: 7-8 Pages: 574-580

    • DOI

      10.1002/psc.2946

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Microwave-Assisted Synthesis of Azacoumarin Fluorophores and the Fluorescence Characterization2017

    • Author(s)
      Hikaru Takano, Tetsuo Narumi, Wataru Nomura, Hirokazu Tamamura
    • Journal Title

      J. Org. Chem.

      Volume: 82 Issue: 5 Pages: 2739-2744

    • DOI

      10.1021/acs.joc.6b02656

    • Related Report
      2017 Annual Research Report 2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Synthesis and Evaluation of Dimeric Derivatives of Diacylglycerol-lactones as PKC Ligands2017

    • Author(s)
      Nami Ohashi, Ryosuke Kobayashi, Wataru Nomura, Takuya Kobayakawa, Agnes Czikora, Brienna Herold, Nancy E. Lewin, Peter M. Blumberg, Hirokazu Tamamura
    • Journal Title

      Bioconjugate Chem.

      Volume: 28 Issue: 8 Pages: 2135-2144

    • DOI

      10.1021/acs.bioconjchem.7b00299

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Stereoselective Synthesis of Xaa-Yaa Type (Z)-Chloroalkene Dipeptide Isosteres via Efficient Utilization of Organocopper Reagents Mediated Allylic Alkylation2017

    • Author(s)
      Kobayakawa T, Tamamura H
    • Journal Title

      Tetrahedron

      Volume: 73 Issue: 30 Pages: 4464-4471

    • DOI

      10.1016/j.tet.2017.06.003

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Small-Molecule CD4 Mimics Containing Mono-cyclohexyl Moieties as HIV Entry Inhibitors.2016

    • Author(s)
      Nami Ohashi1, Shigeyoshi Harada, Takaaki Mizuguchi1, Yu Irahara1, Yuko Yamada, Misato Kotani, Wataru Nomura, Shuzo Matsushita, Kazuhisa Yoshimura, Hirokazu Tamamura.
    • Journal Title

      Chem Med Chem

      Volume: 19 Issue: 8 Pages: 940-946

    • DOI

      10.1002/cmdc.201500590

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A minimally cytotoxic CD4 mimic as an HIV entry inhibitor2016

    • Author(s)
      Takaaki Mizuguchi, Shigeyoshi Harada, Tomoyuki Miura, Nami Ohashi, Tetsuo Narumi, Hiromi Mori, Yu Irahara, Yuko Yamada, Wataru Nomura, Shuzo Matsushita, Kazuhisa Yoshimura, Hirokazu Tamamura
    • Journal Title

      Bioorganic & Medicinal Chemistry Letters

      Volume: 26 Issue: 2 Pages: 397-400

    • DOI

      10.1016/j.bmcl.2015.11.103

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Exploration of Labeling of Near Infrared Dyes on the Polyproline Linker for Bivalent-Type CXCR4 Ligands.2016

    • Author(s)
      Wataru Nomura, Haruo Aikawa, Shohei Taketomi, Miho Tanabe, Takaaki Mizuguchi & Hirokazu Tamamura
    • Journal Title

      Bioorg. Med. Chem.

      Volume: 23 Issue: 21 Pages: 6967-6973

    • DOI

      10.1016/j.bmc.2015.09.040

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Utilization of the Heavy Atom Effect for the Development of a Photosensitive 8-Azacoumarin-Type Photolabile Protecting Group2015

    • Author(s)
      Hikaru Takano, Tetsuo Narumi, Wataru Nomura, Toshiaki Furuta, and Hirokazu Tamamura
    • Journal Title

      Organic Letters

      Volume: 17 Issue: 21 Pages: 5372-5375

    • DOI

      10.1021/acs.orglett.5b02720

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Trivalent Lignds for CXCR4 Bearing Polyproline Linkers Show Specific Recognition for Cells with Increased CXCR4 Expression.2015

    • Author(s)
      Wataru Nomura, Taisuke Koseki, Nami Ohashi, Takaaki Mizuguchi & Hirokazu Tamamura
    • Journal Title

      Org. Biomol. Chem.

      Volume: 13 Issue: 32 Pages: 8734-8739

    • DOI

      10.1039/c5ob00891c

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Anti-HIV Screening for Cell-Penetrating Peptides Using Chloroquine and Identification of Anti-HIV Peptides Derived from Matrix Proteins.2015

    • Author(s)
      Takaaki Mizuguchi, Nami Ohashi, Wataru Nomura, Mao Komoriya, Chie Hashimoto, Naoki Yamamoto, Tsutomu Murakami & Hirokazu Tamamura
    • Journal Title

      Bioorg. Med. Chem.

      Volume: 23 Issue: 15 Pages: 4423-4427

    • DOI

      10.1016/j.bmc.2015.06.020

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] An In-cell Fluorogenic Tag-probe System for Protein Dynamics Imaging Enabled by Cell-Penetrating Peptides.2015

    • Author(s)
      Wataru Nomura, Nami Ohashi, Atsumi Mori & Hirokazu Tamamura
    • Journal Title

      Bioconjugate Chem.

      Volume: 26 Issue: 6 Pages: 1080-1085

    • DOI

      10.1021/acs.bioconjchem.5b00131

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Presentation] Rigid bivalent ligands of the chemokine receptor CXCR4 and their anti-cancer metastasis activity2017

    • Author(s)
      Tamamura H
    • Organizer
      KCS Biochemistry Division Summer Workshop
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Synthesis of chloroalkene dipeptide isosteres as peptidomimetics and their biological application2017

    • Author(s)
      Tamamura H
    • Organizer
      12th Australian Peptide Conference 2017
    • Related Report
      2017 Annual Research Report 2016 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Development of Synthetic Methods for Chloroalkene Dipeptide Isosteres and Their Applications2017

    • Author(s)
      Kobayakawa T, Tamamura H
    • Organizer
      The 25th American Peptide Symposium and the 9th International Peptide Symposium
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Bivalent Ligands of the Chemokine Receptor CXCR4 with Polyproline Linkers and Their Anti-chemotactic Activity2017

    • Author(s)
      Nomura W, Tanaka T, Aoki T, Tamamura H
    • Organizer
      The 25th American Peptide Symposium and the 9th International Peptide Symposium
    • Related Report
      2017 Annual Research Report 2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] CD4 Mimics for Enhancement of Activity of HIV Neutralizing Antibodies2017

    • Author(s)
      Ohashi N, Harada S, Irahara Y, Ishida Y, Konno K, Kobayakawa T, Nomura W, Matsushita S, Yoshimura K, Tamamura H
    • Organizer
      The 11th AFMC International Medicinal Chemistry Symposium
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] HIV外被タンパク質gp41由来ペプチドC34の二量体を基盤とした膜融合阻害剤2016

    • Author(s)
      玉村啓和
    • Organizer
      日本薬学会第136年会シンポジウム「抗ウイルス感染症のフロンティア」
    • Place of Presentation
      パシフィコ横浜、神奈川県横浜市
    • Year and Date
      2016-03-28
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] Multivalent ligands for CXCR4 with polyproline linkers showing specific recognition for its expression2015

    • Author(s)
      玉村啓和
    • Organizer
      The 7th International Peptide Symposium
    • Place of Presentation
      Singapore, Singapore
    • Year and Date
      2015-12-09
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Multivalent ligands showing specific recognition for CXCR4 expression2015

    • Author(s)
      玉村啓和
    • Organizer
      The Seventh Peptide Engineering Meeting (PEM7)
    • Place of Presentation
      Pune, India
    • Year and Date
      2015-12-05
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Peptidomimetic-based Mid-size Drug Research: Anti-HIV Agents2015

    • Author(s)
      玉村啓和
    • Organizer
      The 10th AFMC International Medicinal Chemistry Symposium
    • Place of Presentation
      Jeju, Korea
    • Year and Date
      2015-10-18
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] An anti-HIV assay method for cell-penetrating peptides using chloroquine and identification of inhibitory peptides derived from matrix proteins2015

    • Author(s)
      玉村啓和
    • Organizer
      The 16th Kumamoto AIDS Seminar
    • Place of Presentation
      阿蘇リゾートグランヴィリオホテル、熊本県阿蘇市
    • Year and Date
      2015-10-07
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Development of peptide-lead anti-HIV agents and chemical biology2015

    • Author(s)
      玉村啓和
    • Organizer
      Seminar Series in University of Nebraska Medical Center
    • Place of Presentation
      Omaha, USA
    • Year and Date
      2015-10-02
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] ペプチドを基盤とした中分子創薬研究-抗HIV剤の創製2015

    • Author(s)
      玉村啓和
    • Organizer
      第21回ペプチドフォーラム
    • Place of Presentation
      東京薬科大学サテライトキャンパス、東京都千代田区
    • Year and Date
      2015-08-29
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Book] Mid-Size Drugs Based on Peptides and Peptidomimetics: A New Drug Category2018

    • Author(s)
      Tamamura H, Kobayakawa T, Ohashi N
    • Total Pages
      100
    • Publisher
      Springer
    • Related Report
      2017 Annual Research Report 2016 Annual Research Report
  • [Book] Peptide-derived mid-sized anti-HIV agents. Amino Acids, Peptides and Proteins2017

    • Author(s)
      Ohashi N, Tamamura H
    • Total Pages
      30
    • Publisher
      The Royal Society of Chemistry
    • Related Report
      2017 Annual Research Report

URL: 

Published: 2015-04-16   Modified: 2019-03-29  

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