Medicinal chemistry based peptides against intractable disease including AIDS. Cancer and rheumatoid arthritis

• Project/Area Number: 18390035
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: TAMAMURA Hirokazu Tokyo Medical and Dental University, 生体材料工学研究所, 教授 (80217182)
• Co-Investigator(Kenkyū-buntansha): 堤浩 (堤 浩) 東京医科歯科大学, 生体材料工学の研究所, 助教 (70398105) ; 増野 弘幸 東京医科歯科大学, 生体材料工学研究所, 技術職員 (80376714)
• Project Period (FY): 2006 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥17,560,000 (Direct Cost: ¥14,800,000、Indirect Cost: ¥2,760,000); Fiscal Year 2008: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2007: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2006: ¥5,600,000 (Direct Cost: ¥5,600,000)
• Keywords: ケモカイン / CXCR4 / 癌 / HIV / アンタグニスト / 関節リホマチ / FC131 / T140 / アンタゴニスト / 間節リウマチ / 関節リウマチ / 慢性関節リウマチ

Research Abstract

CXCL12-CXCR4系に関わる難治性疾患を標的として、新規CXCR4アンタグニストをリード化合物とした分子設計および合成に取り組み、T140の誘導体FC131を基盤として、N末端部の新たなpharmachphoreの発見した。FC131に含まれるD-Tyr^3及びArg^4を構造変換のターケットとした設計し、種々の環状ペンタペプチド化合物の合成を行い、CXCR4アンタグニスト活性を有する2種類の環状ペンタペプチドを見出した。これにより新規のファルマコフォアを発見した。また、drug-likeな構造を持った低分子アンタグニDipicolylamine-Zn(II)complex(Dpa-Zn)の開発にも成功した。

Research Products

• [Journal Article] Inhibitory Effect of Newly Developed CXC-Chemokine Receptor 4 Antagonists on the Infection with Feline Immunodeficiency Virus (2009)
  • Author(s): H. Mizukoshi. H. Tamamura, (他8人、7番目)
  • Journal Title: J.Vet.Med.Sci 71(1)巻 Pages: 121-124
  • NAID: 110007055389
  • Peer Reviewed
• [Journal Article] Inhibitory Effect of Newly Developed CXC-Chemokine Receptor 4 Antagonists on the Infection with Feline Immunodeficiency Virus. (2009)
  • Author(s): F. Mizukoshi, H. Tamamura, et al
  • Journal Title: J. Vet. Med, Sci. 71(1) Pages: 121-124
  • NAID: 110007055389
  • Peer Reviewed
• [Journal Article] Modulation of Network-driven, GABA-mediated Giant Depolarizing Potentials by SDF-1 in Developing Hippocampus (2008)
  • Author(s): A. Kasiyanov, N. Fujii, H. Tamamura, H.Xiong,(他0人、3番目)
  • Journal Title: Developmental Neuroscience 34(4) Pages: 285-292
  • Peer Reviewed
• [Journal Article] Development of Peptide-targeted Lipoplexes to CXCR4-expressing Rat Glioma Cells and Rat Proliferating Endothelial Cells (2008)
  • Author(s): W.H.P. Driessen, N. Fujii, H. Tamamura, S. M. Sullivan(他0人、3番目)
  • Journal Title: Mol.Ther 16(3)巻 Pages: 516-524
  • Peer Reviewed
• [Journal Article] Potent SynergisticAnti-Human Immunodeficiency Virus(HIV)Effects Using Combinations of the CCR5 Inhibitor Aplaviroc with Other Anti-HIV Drugs (2008)
  • Author(s): H. Nakatai H. Tamamura, N. Fujii, H. Mits,(他4人、6番目)
  • Journal Title: Antimicrob. Agents Chemother 52(6)巻 Pages: 2111-2119
  • Peer Reviewed
• [Journal Article] Exploratory Studies on Development of the Chemokine Receptor CXCR4 Antagonists toward Downsizing (2008)
  • Author(s): H. Tamamura, H. Tsutsumi, W. Nomura, N. Fujii(他0人、2番目)
  • Journal Title: Perspectives in Medicinal Chemistry 2巻 Pages: 1-9
  • Peer Reviewed
• [Journal Article] A Future Perspective on the Development of Chemokine Receptor CXCR4 Antagonists (2008)
  • Author(s): H. Tamamura, H. Tsutsumi, W. Nomura, T. Tanaka , N. Fujii(他0人、2番目)
  • Journal Title: Expert Opin. Drug Discovery 3(10)巻 Pages: 1155-1166
  • Peer Reviewed
• [Journal Article] Structure-activity Relationship Study of CXCR4 Antagonists Bearing the Cyclic Pentapeptide Scaffold : Identification of the New Pharmacophore (2008)
  • Author(s): T. Tanaka, H. Tsutsumi, W. Nomura, N. Fujii, H. Tamamura(他10人、3番目)
  • Journal Title: Bioconjugate Chem 6(23) Pages: 4374-4377
  • Peer Reviewed
• [Journal Article] Fluorophore Labeling Enables Imaging and Evaluation of Specific CXCR4-Ligand Interaction at the Cell Membrane for Fluorescence-Based Screening (2008)
  • Author(s): W. Nomura, Y. Tanabe, H. Tsutsumi, T. Tanaka, K. Ohba, N. Yamamoto, H. Tamamura(他0人、1番目)
  • Journal Title: Bioconjugate Chem 19巻 Pages: 1917-1920
  • Peer Reviewed
• [Journal Article] Structure-activity Relationship Study of CXCR4 Antagonists Bearing the Cyclic Pentapeptide Scaffold : Identification of the New Pharmacophore (2008)
  • Author(s): T. Tanaka, H. Tamamura, et al.
  • Journal Title: Ore. Biomol. Chem. 6(23) Pages: 4374-4377
  • Peer Reviewed
• [Journal Article] A Future Perspective on the Development of Chemokine ReceptorCXC R4 Antagonists (2008)
  • Author(s): H. Tamamura, et al.
  • Journal Title: Expert Opin. Drug Discovery 3(10) Pages: 1155-1166
  • Peer Reviewed
• [Journal Article] Fluorophore Labeling Enables Imaging and Evaluation of Specific CXCR4-Ligand Interaction at the Cell Membrane for Fluorescence-Based Screening. (2008)
  • Author(s): W. Nomura, H. Tamamura, et al.
  • Journal Title: Bioconjugate Chem. 19 Pages: 1917-1920
  • Peer Reviewed
• [Journal Article] Modulation of Network-driven, GABA-mediated Giant Depolarizing Potentials by SDF-1 in Developing Hippocampus. (2008)
  • Author(s): A. Kasiyanov, N. Fujii, H. Tamamura & H. Xiong.
  • Journal Title: Developmental Neuroscience 30(4) Pages: 285-292
  • Peer Reviewed
• [Journal Article] Development of Peptide-targeted Lipoplexes to CXCR4-expressing Rat Glioma Cells and Rat Proliferating Endothelial Cells. (2008)
  • Author(s): W. H. P. Driessen, H. Tamamura, et al.
  • Journal Title: Mol. Ther. 16(3) Pages: 516-524
  • Peer Reviewed
• [Journal Article] Exploratory Studies on Development of the Chemokine Receptor CXCR4 Antagonists toward Downsizing (2008)
  • Author(s): H. Tamamura, et al.
  • Journal Title: Perspectives in Medicinal Chemistry 2 Pages: 1-9
  • Peer Reviewed
• [Journal Article] Potent Synergistic Anti-Human Immunodeficiency Virus (HIV) Effects Using Combinations of the CCR5 Inhibitor Aplaviroc with Other Anti-HIV Drugs. (2008)
  • Author(s): H. Nakata, H. Tamamura, et al.
  • Journal Title: Antimicrob. Agents Chemother. 52(6) Pages: 2111-2119
  • Peer Reviewed
• [Journal Article] Development of Low Molecular Weight CXCR4 Antagonists by Exploratory Structural Tuning of Cyclic Tetra- and Pentapeptide-scaffolds towards the Treatment of HIV Infection, Cancer Metastasis and Rheumatoid Arthritis (2007)
  • Author(s): H. Tamamura, H. Tsutsumi, H. Masuno, N. Fujii(他0人、1番目)
  • Journal Title: Curr. Med. Chem 14(1)巻 Pages: 93-102
  • Peer Reviewed
• [Journal Article] Structure-Activity Relationships of Cyclic Peptide-Based Chemokine Receptor CXCR4 Antagonists : Disclosing the Importance of Side-Chain and Backbone Functionalities (2007)
  • Author(s): S. Ueda, S. Oishi, Z. Wang, T. Araki, H. Tamamura, N. Fujii(他6人、5番目)
  • Journal Title: J.Med.Chem 50(2)巻 Pages: 192-198
  • Peer Reviewed
• [Journal Article] Rapid Hematopoietic Progenitor Mobilization by Sulfated Colominic Acid (2007)
  • Author(s): S. Kubonishi, T. Kikuchi, S. Yamaguchi, H. Tamamura, N. Fujii, Y. Katayama(他5人、4番目)
  • Journal Title: Biochem.Biophys.Res.Commun 355(4)巻 Pages: 970-975
  • NAID: 120001384686
  • Peer Reviewed
• [Journal Article] Direct Assessment of CXCR4 Mutant Conformations Reveals Complex link between Receptor Structure and Galphai Activation (2007)
  • Author(s): Y A. Berchiche, K. Y. Chow, B. Lagane, M. Leduc, Y. Percherancier, N. Fujii, H. Tamamura, F. Bachelerie, N. Heveker(他0人、7番目)
  • Journal Title: J.Biol.Chem.Commun. 282巻 Pages: 5111-5115
  • Peer Reviewed
• [Journal Article] CXCR4 Engagement Promotes Dendritic Cell Survival and Maturation (2007)
  • Author(s): K. Kabashima, K. Sugita, N. Shiraishi, H. Tamamura, N. Fujii, Y. Tokura(他0人、4番目)
  • Journal Title: Biochem.Biophys.Res.Commun 361巻 Pages: 1012-1016
  • Peer Reviewed
• [Journal Article] CXCL12-CXCR4 Engagement Is Required for Migration of Cutaneous Dendritic Cells (2007)
  • Author(s): K. Kabashima, H. Tamamura, N.Fujii, K. Inaba, Y. Tokura(他7人、9番目)
  • Journal Title: Am.J Pathol 171(4)巻 Pages: 1249-1257
  • Peer Reviewed
• [Journal Article] Versatile Use of Acid-catalyzed Ring-opening of β-Aziridinyl-a, 13-enoatesto Stereoselective Synthesis of Peptidomimetics (2007)
  • Author(s): H. Tamamura, T. Tanaka, H. Tsutsumi, N. Fujii(他4人、3番目)
  • Journal Title: Tetrahedron 63巻 Pages: 9243-9254
  • Peer Reviewed
• [Journal Article] Inhibitors of the Chemokine Receptor CXCR4. Chemotherapy of AIDS, Metastatic Cancer Leukemia and Rheumatoid Arthritis (2007)
  • Author(s): H. Tsutsumi, H. Tamamura, N. Fujii(他0人、1番目)
  • Journal Title: Lett. Drug Design Discovery 4巻 Pages: 20-26
  • Peer Reviewed
• [Journal Article] The Therapeutic Potential of the Chemokine Receptor CXCR4 Antagonists as Multi-functional Agents (2007)
  • Author(s): H. Tsutsumi, H. Tamamura, N. Fujii(他7人、1番目)
  • Journal Title: Biopolymers : Peptide Science 88(2)巻 Pages: 279-289
  • Peer Reviewed
• [Journal Article] Structure-activity relationships of cyclic peptide-based chemokine receptor CXCR4 antagonists: Disclosing the importance of side-chain and backbone functionalities (2007)
  • Author(s): Tamamura H, et. al.
  • Journal Title: J. Med. Chem. 50(2) Pages: 192-198
  • Peer Reviewed
• [Journal Article] Development of low molecular weight CXCR4 antagonists by exploratory structural tuning of cyclic tetra-and pentapeptide-scaffolds to wards the treatment of HIV infection, cancer metastasis and rheumatoid arthritis (2007)
  • Author(s): Tamamura H, et. al.
  • Journal Title: Curr. Med. Chem 14(1) Pages: 93-102
  • Peer Reviewed
• [Journal Article] Inhibitors of the chemokine receptor CXCR4. chemotherapy of AIDS, metastatic cancer, leukemia and rheumatoid arthritis (2007)
  • Author(s): Tamamura H, et. al.
  • Journal Title: Lett. Drug Design Discovery 4 Pages: 20-26
  • Peer Reviewed
• [Journal Article] Specific Probes for Chemokine Receptors (2006)
  • Author(s): H. Tamamura, H. Tsutsumi(他0人、1番目)
  • Journal Title: Chem.Biol 13巻 Pages: 8-10
  • Peer Reviewed
• [Journal Article] HIV-1 gp120 Enhances Giant Depolarizing Potentials via Chemokine Receptor CXCR4 in Neonatal Rat Hippocampus (2006)
  • Author(s): A. Kasyanov, H. Tamamura, N. Fujii, H. Xiong(他0人、2番目)
  • Journal Title: Eur.J.Neuroscience 23巻 Pages: 1120-1128
  • Peer Reviewed
• [Journal Article] A Radiolabeled CXCR4 Inhibitor for Tumor Imaging (2006)
  • Author(s): H. Hanaoka, H.Tamamura, N. Fujii, H. Saji(他6人、3番目)
  • Journal Title: Nucl.Med.Biol 33巻 Pages: 489-494
  • Peer Reviewed
• [Journal Article] The Involvement of Stromal Derived Factor la in Homing and Progression of Multiple Myeloma in the 5TMM Model (2006)
  • Author(s): E. Menu, N. Fujii, H. Tamamura, K. Vanderkerken(他7人、9番目)
  • Journal Title: Haematologica/the Hematology Journal 91巻 Pages: 605-612
  • Peer Reviewed
• [Journal Article] Identification of a New Class of Low Molecular Weight Antagonists against the Chemokine Receptor CXCR4 Having the Dipicolylamine-Zinc(II)Complex Structure (2006)
  • Author(s): H. Tamamura, A. Ojida, H. Tsutsumi, H.Nakashima,N. Yamamoto, I. Hamachi, N. Fujii(他2人、1番目)
  • Journal Title: J Med.Chem 49巻 Pages: 3412-3415
  • Peer Reviewed
• [Journal Article] he Chemokine Receptor CXCR4 as a Therapeutic Target for Several Diseases (2006)
  • Author(s): H. Tamamura, H. Tsutsumi, N. Fujii(他0人、1番目)
  • Journal Title: Mini-Rev Med.Chem 6巻 Pages: 989-995
  • Peer Reviewed
• [Journal Article] Development of a Linear Type of Low Molecular Weight CXCR4 Antagonists Based on T140 Analogs (2006)
  • Author(s): H. Tamamura, H. Tsutsumi, H. Nakashima, N. Yamamoto, S. C. Peiper, N. Fujii(他5人、1番目)
  • Journal Title: Org.Biomol.Chem 4巻 Pages: 2354-2357
  • Peer Reviewed
• [Journal Article] Specific Probes for Chemokine Receptors (2006)
  • Author(s): H.Tamamura, et al.
  • Journal Title: Chem. Biol. 13 Pages: 8-10
• [Journal Article] A Radiolabeled CXCR4 Inhibitor for Tumor Imaging (2006)
  • Author(s): H.Tamamura, et al.
  • Journal Title: Nucl. Med. Biol. 33(4) Pages: 489-494
• [Journal Article] The Involvement of Storomal Derived Factor 1α in Homing and Progression of Multiple Myeloma in the 5TMM Model (2006)
  • Author(s): H.Tamamura, et al.
  • Journal Title: Haematologica/the Hematology Journal 91(5) Pages: 605-612
• [Journal Article] Identification of a New Class of Low Molecular Weight Antagonists agains the Chemokine Receptor CXCR4 Having the Dipicolylamine-Zinc(II) Complex Structure (2006)
  • Author(s): H.Tamamura, et al.
  • Journal Title: J. Med. Chem. 49(11) Pages: 3412-3415
• [Journal Article] The Chemokine Receptor CXCR4 as a Therapeutic Target for Several Diseases (2006)
  • Author(s): H.Tamamura, et al.
  • Journal Title: Mini-Rev. Med. Chem. 6 Pages: 989-995
• [Journal Article] Development of a Linear Type of Low Molecular Weight CXCR4 Antagonists Based on T140 Analogs (2006)
  • Author(s): H.Tamamura, et al.
  • Journal Title: Org. Biomol. Chem. 4 Pages: 2354-2357
• [Presentation] 抗HlV剤を中心とした創薬基礎研究 (2008)
  • Author(s): 玉村啓和
  • Organizer: 日本薬学会関東支部 第22回シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2008-11-15
• [Presentation] Barry Evans, Zi-xuan Wng, Stephen C peiper, 玉村智和, 新規ファルマコフォアを有するケモカインレセプターCXCR4アンタゴニストの構造活性相関研究 (2008)
  • Author(s): 田中智博, 玉村啓和など
  • Organizer: 日本ケミカルバイオロジー研究会第3回集会
  • Place of Presentation: 東京
• [Presentation] 環状ペンタベンチド骨格を有するCXCR4アンタゴニストの構造活性相関研究 : 新規ファルマコフォアの固定 (2008)
  • Author(s): 田中智博, 玉村啓和など
  • Organizer: 第45回ペプチド討論会
  • Place of Presentation: 東京
• [Presentation] 蛍光性CXCR4特異的プローブのスクリーニング及びイメージングへの応用 (2008)
  • Author(s): 田中智博, 玉村啓和など
  • Organizer: 第45回ペプチド討論会
  • Place of Presentation: 東京
• [Presentation] 種々の作用点をターゲットした抗HIV剤の創製 (2008)
  • Author(s): 玉村啓和
  • Organizer: 第22回エイズ学会
  • Place of Presentation: 大阪
• [Presentation] Rerouting the plasma membrane targeting of HIV-1 and MLV gag by replacing myristoylation signal with membrane proteins (2007)
  • Author(s): T. Aoki, H. Tmamura, et.al.
  • Organizer: Cold Spring Harbor Laboratory Meetings & Courses Retroviruses
  • Place of Presentation: New York, USA
  • Year and Date: 2007-05-23
• [Presentation] Stereoselective synthesis of peptidomimetics based on acid-catalyzed ring-opening of beta-aziridinyl-alpha, beta-enoates (2007)
  • Author(s): H. Tamamura, et.al.
  • Organizer: 20th American Peptide Symposium
  • Place of Presentation: Montreal, Canada
• [Presentation] Development of chemokine receptor CXCR4 antagonists using bio-mimetic strategy (2007)
  • Author(s): H. Tamamra, et.al.
  • Organizer: 20th American Peptide Symposium
  • Place of Presentation: Montreal, Canada
• [Presentation] Identification of sequential motifs relevant to inhibitory activity against HIV integrase (2007)
  • Author(s): H. Tamamara, et.al.
  • Organizer: 4th International Peptide Symposium,
  • Place of Presentation: Cairns Australia
• [Presentation] Chemical synthesis of a PKC Clb domain by a peptide ligation method and expression of the protein in (2007)
  • Author(s): N. Ohashi, H. Tamamura, et.al.
  • Organizer: coli and their application. 4th International Peptide Symposium
  • Place of Presentation: Cairns, Australia
• [Presentation] A Potent neutralizing anti-V3 monoclonal antibody, KD-247 shows favorable synergism with other antiretrovirals, Scd4 and CD4 mimic small compound in vitro (2007)
  • Author(s): K. Yoshimura, H. Tamaura, et.al.
  • Organizer: 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention
  • Place of Presentation: Sydney, Australia
• [Book] Peptide Science 2007 (2008)
  • Author(s): H. Tamamura, et al.
  • Total Pages: 4
  • Publisher: The Japanese peptide Society
• [Patent(Industrial Property Rights)] 標的物質の検出方法、並びに、これに用いるタグ、DNA、ベクター、プローブ及び検出キット (2008)
  • Inventor(s): 玉村啓和、堤浩
  • Industrial Property Rights Holder: 国立大学法人東京医科歯科大学
  • Filing Date: 2008-03-24
  • Overseas