Development of early diagnostic methods for cancer tissue and metastasis utilizing bivalent GPCR ligands

• Project/Area Number: 24390024
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: Tokyo 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): NOMURA Wataru 東京医科歯科大学, 生体材料工学研究所, 准教授 (80463909) ; NARUMI Testuo 東京医科歯科大学, 生体材料工学研究所, 助教 (50547867) ; AIKAWA Haruo 東京医科歯科大学, 生体材料工学研究所, 特任助教 (70547322)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥18,850,000 (Direct Cost: ¥14,500,000、Indirect Cost: ¥4,350,000); Fiscal Year 2014: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2013: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2012: ¥9,880,000 (Direct Cost: ¥7,600,000、Indirect Cost: ¥2,280,000)
• Keywords: 分子標的 / GPCR / 分子プローブ / 創薬ツール / ケモカインレセプターCXCR4 / ２価結合型リガンド / 認識ユニット / がん / 2価結合型リガンド

Outline of Final Research Achievements

The assembly status of G protein-coupled receptors (GPCR) on the cellular surface is of interest because the multimerization of GPCR could play pivotal roles in cellular functions. A bivalent ligand with polyproline linkers for CXCR4 has been shown to serve as “molecular ruler” as a result of the rigid structure of polyproline helices. To expand the utility of the ligands with rigid linkers and explore the possible multimeric forms of GPCR, ligands with polyproline helices were newly designed and synthesized. The binding affinities of ligands for CXCR4 suggested that the ligands recognize the dimeric form of CXCR4 on the cellular surface. The fluorescent imaging and analysis by flow cytometry revealed that the ligand with 9-proline linkers binds to CXCR4 with remarkable specificity. The results of the present study suggest that the ligand design with rigid linkers is useful in the multimeric form.

Research Products

• [Journal Article] Screening for Protein Kinase C Ligands Using Fluorescence Resonance Energy Transfer. (2014)
  • Author(s): Nami Ohashi, Wataru Nomura, Natsuki Minato & Hirokazu Tamamura
  • Journal Title: Chem. Pharm. Bull., Volume: 62-10 Pages: 1019-1025
  • NAID: 130004677396
  • Peer Reviewed / Open Access
• [Journal Article] Development of a Fluoride-responsive Amide Bond Cleavage Device that is Potentially Applicable to a Traceable Linker. (2014)
  • Author(s): 5.Jun Yamamoto, Nami Maeda, Chiaki Komiya, Tomohiro Tanaka, Masaya Denda, Koji Ebisuno, Wataru Nomura, Hirokazu Tamamura, Youichi Sato, Aiko Yamauchi, Akira Shigenaga & Akira Otaka
  • Journal Title: Tetrahedron, Volume: 70-34 Pages: 5122-5127
  • NAID: 120006493358
  • Peer Reviewed / Open Access
• [Journal Article] CXCR4-derived synthetic peptides inducing anti-HIV-1 antibodies. (2013)
  • Author(s): Hashimoto C, Nomura W, Narumi T, Fujino M, Nakahara T, Yamamoto N, Murakami T, Tamamura H.
  • Journal Title: Bioorg. Med. Chem. Volume: 21 Issue: 22 Pages: 6878-6885
  • DOI: 10.1016/j.bmc.2013.09.037
  • Peer Reviewed
• [Journal Article] Cell-Permeable Stapled Peptides Based on HIV-1 Integrase Inhibitors Derived from HIV-1 Gene Products. (2013)
  • Author(s): Nomura W, Aikawa H, Ohashi N, Urano E, Metifiot M, Fujino M, Maddali K, Ozaki T, Nozue A, Narumi T, Hashimoto C, Tanaka T, Pommier Y, Yamamoto N, Komano JA, Murakami T, Tamamura H.
  • Journal Title: ACS Chem. Biol. Volume: 8 Issue: 10 Pages: 2235-2244
  • DOI: 10.1021/cb400495h
  • Peer Reviewed
• [Journal Article] Anti-HIV-1 Peptide Derivatives Based on the HIV-1 Co-receptor CXCR4. (2013)
  • Author(s): Hashimoto C, Nomura W, Narumi T, Fujino M, Tsutsumi H, Haseyama M, Yamamoto N, Murakami T, Tamamura H.
  • Journal Title: ChemMedChem Volume: 8 Issue: 10 Pages: 1668-1672
  • DOI: 10.1002/cmdc.201300289
  • Peer Reviewed
• [Journal Article] Low Molecular Weight CXCR4 Ligands with Variable Spacers. (2013)
  • Author(s): Narumi, T., Aikawa, H., Tanaka, T., Hashimoto、C., Ohashi, N., Nomura, W., Kobayakawa, T., Takano, H., Hirota, Y., Murakami, T., Yamamoto, N. and Tamamura, H.
  • Journal Title: ChemMedChem Volume: 8 Issue: 1 Pages: 118-124
  • DOI: 10.1002/cmdc.201200390
  • Peer Reviewed
• [Journal Article] Pharmacophore-Based Small Molecule CXCR4 Ligands. (2012)
  • Author(s): Narumi, T., Tanaka, T., Hashimoto, C., Nomura, W., Aikawa, H., Sohma, A., Itotani, K., Kawamata, K., Murakami, T., Yamamoto, N. and Tamamura, H.
  • Journal Title: Bioorg.Med. Chem. Lett. Volume: 22 Issue: 12 Pages: 4169-4172
  • DOI: 10.1016/j.bmcl.2012.04.032
  • Peer Reviewed
• [Journal Article] Synthetic C34 Trimer of HIV-1 gp41 Shows Significant Increase of Inhibition Potency (2012)
  • Author(s): W.Nomura, T.Tanaka, et.al.
  • Journal Title: Chem Med Chem Volume: 7 Issue: 2 Pages: 205-208
  • DOI: 10.1002/cmdc.201100542
  • Peer Reviewed
• [Presentation] “Multimerized Peptides Derived from the C-Terminal Region of HIV-1 gp41 as Fusion Inhibitors” (2014)
  • Author(s): Nomura W, Hashimoto C, Fujino M, Murakami T, Ohashi N, Tamamura H.
  • Organizer: The 33rd European Peptide Society Symposium.
  • Place of Presentation: Sofia, Bulgaria,
  • Year and Date: 2014-08-31 – 2014-09-05
• [Presentation] “Efficient Gene Disruption at hTERT Promoter Region by Simultaneous Digestion by Pairs of ZFNs or Guide RNAs of CRISPR/Cas System” (2014)
  • Author(s): Nomura W, Masuda A, Tamamura H.
  • Organizer: The 28th Annual Symposium of the Protein Society.
  • Place of Presentation: San Diego, USA,
  • Year and Date: 2014-07-27 – 2014-07-30
• [Book] ベプチド医薬の最前線「監修 木曽良明・向井秀仁」 (2012)
  • Author(s): 野村渉、田中智博、玉村啓和
  • Publisher: 株式会社 シーエムシー出版 東京
• [Remarks]
  • URL: http://www.tmd.ac.jp/i-med/www/molb/molb-j.html