Exploration of alpha helix domains for drug target

• Project/Area Number: 26670326
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Hygiene and public health
• Research Institution: The University of Tokyo
• Principal Investigator: Terashima Yuya 東京大学, 医学(系)研究科(研究院), 助教 (90538729)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: GPCR / 創薬標的 / ペプチド / 創薬 / ケモカイン受容体

Outline of Final Research Achievements

The alpha-helix plays an important role for protein-protein interaction and cellular functions. We searched for alpha-helix sequences which serve as a drug target as well as an inhibition tool for the target function by its synthesized peptide of the corresponding sequence with the membrane permeable property. We identified two peptides which inhibit cellular chemotaxis when combined with the membrane permeable sequence. The fact that one amino-acid substitution with hydrophobic residue substantially enhanced its inhibition ability indicates that it functions inside the cell and its hydrophobicity is important for its ability to inhibit chemotaxis. The strategy established in this study can be applicable for broad target proteins and the identified peptides are promising therapeutic tool to inhibit disease-related chemotaxis.

Research Products

• [Journal Article] ケモカインシグナル (2015)
  • Author(s): 遠田悦子、寺島裕也、松島綱治
  • Journal Title: 生体の科学 Volume: 66 Pages: 412-413
• [Journal Article] Robust anti-tumor effects of combined anti-CD4 depleting antibody and anti-PD-1/PD-L1immune checkpoint antibody treatment in mice. (2015)
  • Author(s): Ueha S, Yokochi S, Ishiwata Y, Ogiwara H, Chand K, Nakajima T, Hachiga K,Shichino S, Terashima Y, Toda E, Shand FH, Kakimi K, Ito S, Matshushima K.
  • Journal Title: Cancer Immunol Res. Volume: Epub ahead of print Issue: 6 Pages: 631-640
  • DOI: 10.1158/2326-6066.cir-14-0190
  • Peer Reviewed
• [Journal Article] Robust anti-tumor effects of combined anti-CD4 depleting antibody and anti-PD-1/PD-L1 immune checkpoint antibody treatment in mice. (2015)
  • Author(s): Ueha S, Yokochi S, Ishiwata Y, Ogiwara H, Chand K, Nakajima T, Hachiga K, Shichino S, Terashima Y, Toda E, Shand FH, Kakimi K, Ito S, Matshushima K.
  • Journal Title: Cancer Immunol Res. Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Structural basis for the binding of the membrane-proximal C-terminal region of chemokine receptor CCR2 with the cytosolic regulator FROUNT (2014)
  • Author(s): Esaki K, Yoshinaga S, Tsuji T, Toda E, Terashima Y, Saitoh T, Kohda D, Kohno T, Osawa M, Ueda T, Shimada I, Matsushima K, Terasawa H
  • Journal Title: FEBS J Volume: 281 Issue: 24 Pages: 552-566
  • DOI: 10.1111/febs.13096
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Identification of a binding element for the cytoplasmic regulator FROUNTin the membrane-proximal C-terminal region of chemokine receptors CCR2 and CCR5. (2014)
  • Author(s): Toda E, Terashlma Y, Esakii K, Yoshinaga S, Sugihara M, Kofuku Y, Shimada I, Suwa M, Kanegasaki S, Terasawa H, Matsushima K.
  • Journal Title: Biochemical Journal Volume: Vol.457 Issue: 2 Pages: 313-322
  • DOI: 10.1042/bj20130827
  • Peer Reviewed
• [Presentation] A chemokine receptor-associating molecule FROUNT is required for macrophage infiltraion and tumor progression. (2015)
  • Author(s): Yuya Terashima, Etsuko Toda, and Kouji Matsushima
  • Organizer: International Conference of Cancer Immunotherapy and Macrophages (ICCIM) 2015
  • Place of Presentation: Tokyo
  • Year and Date: 2015-07-09
  • Int'l Joint Research
• [Presentation] Intracellular blockade of chemotaxis via targeting GPCR helix8-associating molecule FROUNT (2015)
  • Author(s): Yuya Terashima, Etsuko Toda, and Kouji Matsushima
  • Organizer: Keystone Synposia; The Biological Code of Cell Signaling
  • Place of Presentation: Steamboat Springs, Colorado USA
  • Year and Date: 2015-01-01 – 2015-01-16
• [Presentation] A chemokine receptor-associating molecule, FROUNT is required for tumor metastasis by regulating tumor microenvironment (2014)
  • Author(s): Yuya Terashima and Kouji Matsushima
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-09-25 – 2014-09-27