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Macrocycles to target influenza viral hemagglutinin as bifunctional potent broad-spectrum antiviral agent

Research Project

Project/Area Number 15K15146
Research Category

Grant-in-Aid for Challenging Exploratory Research

Allocation TypeMulti-year Fund
Research Field Virology
Research InstitutionTokyo Metropolitan Institute of Medical Science

Principal Investigator

KOHARA Michinori  公益財団法人東京都医学総合研究所, ゲノム医科学研究分野, 特任研究員 (10250218)

Project Period (FY) 2015-04-01 – 2018-03-31
Project Status Completed (Fiscal Year 2017)
Budget Amount *help
¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Keywords特殊環状ペプチド / 治療 / インフルエンザ / 高病原性鳥インフルエンザ / 病態抑制機序 / 高病原性トリインフルエンザウイルス / ウイルス / 感染症 / 微生物 / 免疫学
Outline of Final Research Achievements

HA-targeted antibodies have the potential to neutralize HA-mediated virion-cell binding. To devise smaller molecules capable of binding to the influenza viral HA and have the potential as an antiviral agent, we used an emerging technology, RaPID system. After five rounds of selection, we found an appreciable increase in the cDNA recovery rate and sequencing of 69 molecular clones from the selected cDNAs revealed a total of 28 candidates for inhibitor HA (iHA). In order to investigate the influence of iHA-100 on the pathology of H5N1 infection, a comprehensive analysis of cytokines was performed. Inflammatory cytokines (IFN-ganma, IL-6) in the lung of iHA-100-treated monkeys were significantly reduced. These results suggest that H5N1-induced inflammation and pathogenesis was suppressed by administration of iHA-100. iHA-100 is a promising antiviral agent that exhibited the inhibitory effect of both virus replication and pathogenesis in vivo.

Report

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

    (24 results)

All 2017 2016 2015 Other

All Journal Article (12 results) (of which Int'l Joint Research: 6 results,  Peer Reviewed: 11 results,  Open Access: 10 results,  Acknowledgement Compliant: 3 results) Presentation (10 results) (of which Int'l Joint Research: 3 results) Remarks (2 results)

  • [Journal Article] Selective inhibitor of Wnt/β-catenin/CBP signaling ameliorates hepatitis C virus-induced liver fibrosis in mouse model2017

    • Author(s)
      Yuko Tokunaga, Yosuke Osawa, Takahiro Ohtsuki, Yukiko Hayashi, Kenzaburo Yamaji, Daisuke Yamane, Mitsuko Hara, Keisuke Munekata, Kyoko Tsukiyama-Kohara, Tsunekazu Hishima, Soichi Kojima, Kiminori Kimura, and *Michinori Kohara
    • Journal Title

      Scientific Reports

      Volume: 7 Issue: 1 Pages: 325-325

    • DOI

      10.1038/s41598-017-00282-w

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Efficacy of recombinant measles virus expressing highly pathogenic avian influenza virus (HPAIV) antigen against HPAIV infection in monkeys2017

    • Author(s)
      Fujiyuki Tomoko、Horie Ryo、Yoneda Misako、Kuraishi Takeshi、Yasui Fumihiko、Kwon Hyun-jeong、Munekata Keisuke、Ikeda Fusako、Hoshi Miho、Kiso Yuri、Omi Mio、Sato Hiroki、Kida Hiroshi、Hattori Shosaku、Kohara Michinori、Kai Chieko
    • Journal Title

      Scientific Reports

      Volume: 7 Issue: 1 Pages: 12017-12017

    • DOI

      10.1038/s41598-017-08326-x

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Safety, Tolerability, and Preliminary Efficacy of the Anti-Fibrotic Small Molecule PRI-724, a CBP/β-Catenin Inhibitor, in Patients with Hepatitis C Virus-related Cirrhosis: A Single-Center, Open-Label, Dose Escalation Phase 1 Trial.2017

    • Author(s)
      2.Kimura K, Ikoma A, Shibakawa M, Shimoda S, Harada K, Saio M, Imamura J, Osawa Y, Kimura M, Nishikawa K, Okusaka T, Morita S, Inoue K, Kanto T, Todaka K, Nakanishi Y, Kohara M, Mizokami M.
    • Journal Title

      EBioMedicine

      Volume: 23 Pages: 79-87

    • DOI

      10.1016/j.ebiom.2017.08.016

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Susceptibility and initial immune response of Tupaia belangeri cells to dengue virus infection2017

    • Author(s)
      Kayesh MEH, Kitab B, Sanada T, Hayasaka D, Morita K, Kohara M, *Tsukiyama-Kohara K.
    • Journal Title

      Infect Genet Evol.

      Volume: 51 Pages: 203-210

    • DOI

      10.1016/j.meegid.2017.04.003

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Immature Core protein of hepatitis C virus induces an unfolded protein response through inhibition of ERAD-L in a yeast model system2016

    • Author(s)
      Takahashi S, Sato N, Kikuchi J, Kakinuma H, Okawa J, Masuyama Y, Iwasa S, Irokawa H, Hwang GW, Naganuma A, Kohara M, *Kuge S.
    • Journal Title

      Genes Cells

      Volume: 22 Issue: 2 Pages: 160-173

    • DOI

      10.1111/gtc.12464

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Transmission of HBV-DNA mediated by ceramide-triggered extracellular vesicles2016

    • Author(s)
      Takahiro Sanada, Yuichi Hirata, Yutaka Naito, Naoki Yamamoto, Yoshiaki Kikkawa, Yuji Ishida, Chihiro Yamasaki, Chise Tateno, Takahiro Ochiya, and *Michinori Kohara
    • Journal Title

      Cellular and Molecular Gastroenterology and Hepatology

      Volume: 3 Issue: 2 Pages: 272-283

    • DOI

      10.1016/j.jcmgh.2016.10.003

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Sensitization with vaccinia virus harboring hemagglutinin recovers the immune potential against highly pathogenic H5N1 influenza virus in non-human primates2016

    • Author(s)
      Fumihiko Yasui, Yasushi Itoh, Ai Ikejiri, Masahiro Kitabatake, Nobuo Sakaguchi, Keisuke Munekata, Shintaro Shichinohe, Yukiko Hayashi, Hirohito Ishigaki, Misako Nakayama, Yoshihiro Sakoda, Hiroshi Kida, Kazumasa Ogasawara, *Michinori Kohara
    • Journal Title

      Scientific Reports

      Volume: 6 Issue: 1 Pages: 37915-37915

    • DOI

      10.1038/srep37915

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Enhancement of anti-STLV-1/HTLV-1 immune responses through multimodal effects of anti-CCR4 antibody.2016

    • Author(s)
      Sugata K, Yasunaga JI, Miura M, Akari H, Utsunomiya A, Nosaka K, Watanabe Y, Suzushima H, Koh KR, Nakagawa M, Kohara M, Matsuoka M.
    • Journal Title

      Scientific report

      Volume: 6 Issue: 1 Pages: 27150-27150

    • DOI

      10.1038/srep27150

    • NAID

      120005825906

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Property of hepatitis B virus replication in Tupaia belangeri hepatocytes2016

    • Author(s)
      Takahiro Sanada, Kyoko Tsukiyama-Kohara, Naoki Yamamoto, Sayeh Ezzikouri, Soumaya Benjelloun, Shuko Murakami, Yasuhito Tanaka, Chise Tateno, and Michinori Kohara
    • Journal Title

      Biochem Biophys Res Commun

      Volume: 469 Issue: 2 Pages: 229-235

    • DOI

      10.1016/j.bbrc.2015.11.121

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Serum DHCR24 Auto-antibody as a new Biomarker for Progression of Hepatitis C.2015

    • Author(s)
      Ezzikouri S, Kimura K, Sunagozaka H, Kaneko S, Inoue K, Nishimura T, Hishima T, Kohara M, Tsukiyama-Kohara K.
    • Journal Title

      EBioMedicine

      Volume: Apr 13;2(6) Issue: 6 Pages: 604-12

    • DOI

      10.1016/j.ebiom.2015.04.007

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A Multifunctional Envelope-type Nano Device Containing A pH-sensitive Cationic Lipid for Efficient Delivery of Short Interfering RNA to Hepatocytes in Vivo2015

    • Author(s)
      Yusuke Sato, Hideyoshi Harashima and Michinori Kohara
    • Journal Title

      Methods in Molecular Biology

      Volume: 7 Pages: 71-78

    • Related Report
      2015 Research-status Report
  • [Journal Article] M2 macrophages play critical roles in progression of inflammatory liver disease in hepatitis C virus transgenic mice.2015

    • Author(s)
      1.Ohtsuki T, Kimura K, Tokunaga Y, Tsukiyama-Kohara K, Tateno C, Hayashi Y, Hishima T, Kohara M
    • Journal Title

      J Virol

      Volume: Oct 14;90(1) Issue: 1 Pages: 300-7

    • DOI

      10.1128/jvi.02293-15

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] 弱毒化ワクシニアウイルスDIs株を母体とした組換えH5亜型HAインフルエンザワクチンによる発症防御機序の解析2017

    • Author(s)
      安井文彦、宗片圭佑、本田智子、伊藤靖、迫田義博、喜田宏、阪口薫雄、小笠原一誠、小原道法
    • Organizer
      第21回日本ワクチン学会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Elucidation of mechanism undergoing elimination of HPAI H5N1 virus in mice vaccinated with recombinant H5 vaccine based on vaccinia virus vector2017

    • Author(s)
      Yasui F., Munekata K., Honda T., Itoh Y., Sakoda Y., Kida H., Sakaguchi N., Ogasawara K., Kohara M.
    • Organizer
      2017 International Society for Vaccines (ISV) Annual Congress
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] H5N1高病原性鳥インフルエンザウイルスのシアル酸非依存的な細胞侵入経路の解析2017

    • Author(s)
      梶原直樹、野村奈美子、宇梶麻紗子、貞任大地、山本直樹、小原道法、安井文彦、迫田義博、喜田宏、芝崎太
    • Organizer
      第40回日本分子生物学会
    • Related Report
      2017 Annual Research Report
  • [Presentation] インフルエンザウイルス感染阻害活性を示すヘマグルチニン結合性特殊環状ペプチド2016

    • Author(s)
      斉藤 誠、安井文彦、棟方 翼、飛田良美、小澤 真、小原恭子、伊藤利紗、菅 裕明、窪田規一、小原道法
    • Organizer
      第39回日本分子生物学会
    • Place of Presentation
      パシフィコ横浜 (神奈川県横浜市)
    • Year and Date
      2016-11-30
    • Related Report
      2016 Research-status Report
  • [Presentation] ワクチニアウイルスDls株を母体としたインフルエンザHA組換えワクチンのカニクイザルでの八章防御効果の検討2016

    • Author(s)
      宗片圭祐、安井文彦、伊藤 靖、石井孝司、喜田 宏、小笠原一誠、小原道法
    • Organizer
      第20回日本ワクチン学会学術集会
    • Place of Presentation
      京王プラザホテル(東京都新宿区)
    • Year and Date
      2016-10-22
    • Related Report
      2016 Research-status Report
  • [Presentation] Prevention effect of H5N1 HPAI and H1N1 pdm2009 influenza vaccine based on highly attenuated vaccinia virus vector in cynomolgus monkeys2016

    • Author(s)
      Munekata K., Yasui F., Itoh Y., Ishii K., Sakoda Y., Kida H., Ogasawara K., Kohara M.
    • Organizer
      10th Vaccine Congress
    • Place of Presentation
      Amsterdam, the Netherlands
    • Year and Date
      2016-09-04
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] Efficacy of recombinant measles virus expressing highly pathogenic avian influenza virus antigen in non-human primate model2015

    • Author(s)
      Tomoko Fujiyuki, Ryo Horie, Misako Yoneda, Takeshi Kuraishi, Fumihiko Yasui, Hyun-jeong Kwon, Fusako Ikeda, Keisuke Munekata, Miho Ishii, Yuri Kiso, Mio Omi, Hiroki Sato, Hiroshi Kida, Shosaku Hattori, Michinori Kohara, Chieko Kai
    • Organizer
      第63回日本ウイルス学会学術集会
    • Place of Presentation
      福岡国際会議場(福岡県・福岡市)
    • Year and Date
      2015-11-22
    • Related Report
      2015 Research-status Report
  • [Presentation] Highly pathogenic avian influenza A H5N1 virus causes severe symptoms due to insufficient interaction of dendritic cells with T cells2015

    • Author(s)
      Ai Ikejiri, Fumihiko Yasui, Yasushi Itoh, Masahiro Kitabatake, Nobuo Sakaguchi, Kazumasa Ogasawara, Michinori Kohara
    • Organizer
      第44回日本免疫学会
    • Place of Presentation
      札幌コンベンションセンター(北海道・札幌)
    • Year and Date
      2015-11-18
    • Related Report
      2015 Research-status Report
  • [Presentation] H5N1高病原性鳥インフルエンザウイルス感染に対する液性免疫低応答機序とインフルエンザ組換え生ワクチン接種による応答性の回復2015

    • Author(s)
      尻 藍、安井文彦、伊藤 靖、宗方圭祐、阪口薫雄、迫田義博、喜田 宏、小笠原一誠、小原道法
    • Organizer
      第19回ワクチン学会
    • Place of Presentation
      名鉄犬山ホテル(愛知県犬山市)
    • Year and Date
      2015-11-14
    • Related Report
      2015 Research-status Report
  • [Presentation] Highly pathogenic avian influenza virus (H5N1) causes severe symptoms due to insufficient induction of humoral immune responses2015

    • Author(s)
      Ai Ikejiri, Fumihiko Yasui, Nobuo Sakaguchi, Kazumasa Ogasawara, Michinori Kohara
    • Organizer
      4th European Congress of Immunology
    • Place of Presentation
      Vienna (Austria)
    • Year and Date
      2015-09-06
    • Related Report
      2015 Research-status Report
    • Int'l Joint Research
  • [Remarks] インフルエンザ及びB型・C型肝炎ウイルス感染症の予防と治療プロジェクト

    • URL

      http://www.igakuken.or.jp/project/detail/infectious.html

    • Related Report
      2017 Annual Research Report
  • [Remarks] 東京都医学総合研究所

    • URL

      http://www.igakuken.or.jp

    • Related Report
      2015 Research-status Report

URL: 

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

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