iHA-100 exhibited a high efficacy whether administered during the early phase or late phase of H5N1 infection

• Project/Area Number: 15H04739
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Virology
• Research Institution: Tokyo 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)
• Co-Investigator(Kenkyū-buntansha): 齊藤 誠 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, 研究員 (20433021) ; 徳永 優子 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, 研究員 (80555011)
• Research Collaborator: MUNAKTA Tsubasa ; IMAI Yumiko
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2017: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2015: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: ウイルス / 感染症 / 微生物 / 免疫学 / 特殊環状ペプチド / インフルエンザウイルス / 増殖抑制

Outline of Final Research Achievements

Most anti-influenza drugs currently used, such as oseltamivir and zanamivir, inhibit the enzymatic activity of neuraminidase (NA). NA inhibitor-resistant viruses, however, have already been isolated among seasonal H1N1, pandemic (H1N1) 2009, and even highly pathogenic avian H5N1 viruses. These resistant viruses can only be controlled by a new antiviral with a mechanism of action that is totally different from NA inhibition. The recent development of the Random non-standard Peptides Integrated Discovery (RaPID) system enables the identification of high-affinity ligands for a protein of interest from easily prepared libraries consisting of over a trillion macrocyclic peptides. Here we report bi-functional, tropic macrocycles that bind the influenza viral envelope protein hemagglutinin and inhibit virus infection by blocking adsorption and fusion. They showed powerful efficacy in preventing severe pneumonia at later stages of infection in mouse and non-primate cynomolgus macaque models.

Academic Significance and Societal Importance of the Research Achievements

次世代の抗体医薬として、従来抗体が結合し得ない抗原領域を認識することが可能な特殊環状ペプチドに着目した。H5N1インフルエンザウイルスHA蛋白質に対して結合する特殊環状ペプチドiHA100を創成し、マウスにおいてリレンザでは治療効果を示さない感染４日後および６日後からの投与においても治療効果を示した。さらに霊長類感染モデルとしてカニクイザルに高病原性H5N1インフルエンザ感染時の発症防御効果を検討したところ良好な結果が得られ、iHA100は新規インフルエンザ治療薬の可能性が示された。これらHAウイルス蛋白質の選択的な認識・排除機構を解明し、さらなる治療薬の最適化や治療法の確立につなげる。

Research Products

• [Journal Article] Avian H5N1 influenza virus infection causes severe pneumonia in the Northern tree shrew (Tupaia belangeri) (2019)
  • Author(s): Takahiro Sanada, Fumihiko Yasui, Tomoko Honda, Mohammad Enamul Hoque Kayesh, Jun-ichiro Takano, Yumiko Shiogama, Yasuhiro Yasutomi, Kyoko Tsukiyama-Kohara, and Michinori Kohara
  • Journal Title: Virology Volume: 529 Pages: 101-110
  • DOI: 10.1016/j.virol.2019.01.015
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Experimental in vitro and in vivo systems for studying the innate immune response during dengue virus infections (2018)
  • Author(s): Bouchra Kitab, Michinori Kohara and Kyoko Tsukiyama-Kohara
  • Journal Title: Archives of Virology Volume: 163 Issue: 7 Pages: 1717-1726
  • DOI: 10.1007/s00705-018-3784-z
  • Peer Reviewed / Open Access
• [Journal Article] MicroRNA-451a in extracellular, blood-resident vesicles attenuates macrophage and dendritic cell responses to influenza whole-virus vaccine (2018)
  • Author(s): Masaaki Okamoto, Yoshimi Fukushima, Takahisa Kouwaki, Takuji Daito, Michinori Kohara, Hiroshi Kida, Hiroyuki, Oshiumi
  • Journal Title: Journal of Biological Chemistry Volume: 293 Issue: 48 Pages: 18585-18600
  • DOI: 10.1074/jbc.ra118.003862
  • Peer Reviewed
• [Journal Article] Efficacy of recombinant measles virus expressing highly pathogenic avian influenza virus (HPAIV) antigen against HPAIV infection in monkeys (2017)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Oxidative Stress and Immune Responses During Hepatitis C Virus Infection in Tupaia belangeri (2017)
  • Author(s): Kayesh Mohammad Enamul Hoque、Ezzikouri Sayeh、Sanada Takahiro、Chi Haiying、Hayashi Yukiko、Rebbani Khadija、Kitab Bouchra、Matsuu Aya、Miyoshi Noriaki、Hishima Tsunekazu、Kohara Michinori、Tsukiyama-Kohara Kyoko
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 9848-9848
  • DOI: 10.1038/s41598-017-10329-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Broad-spectrum antiviral agents: secreted phospholipase A2 targets viral envelope lipid bilayers derived from the endoplasmic reticulum membrane (2017)
  • Author(s): Ming Chen, Chie Aoki-Utsubo, Masanori Kameoka, Lin Deng, Yutaka Terada, Wataru Kamitani, Kei Sato, Yoshio Koyanagi, Makoto Hijikata, Keiko Shindo, Takeshi Noda, Michinori Kohara & Hak Hotta.
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 15931-15931
  • DOI: 10.1038/s41598-017-16130-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Susceptibility and initial immune response of Tupaia belangeri cells to dengue virus infection (2017)
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Selective inhibitor of Wnt/β-catenin/CBP signaling ameliorates hepatitis C virus-induced liver fibrosis in mouse model (2017)
  • 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
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Transmission of HBV-DNA mediated by ceramide-triggered extracellular vesicles (2016)
  • 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
  • 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 primates (2016)
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Novel pH-sensitive multifunctional envelope-type nanodevice for siRNA-based treatments for chronic HBV infection (2016)
  • Author(s): Yamamoto, N. Sato, Y. Munakata, T. Kakuni, M. Tateno, C. Sanada, T. Hirata, Y. Murakami, S. Tanaka, Y. Chayama, K. Hatakeyama, H. Hyodo, M. Harashima, H. Kohara, M.
  • Journal Title: Journal of hepatology Volume: 64 Issue: 3 Pages: 547-455
  • DOI: 10.1016/j.jhep.2015.10.014
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Property of hepatitis B virus replication in Tupaia belangeri hepatocytes (2016)
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 3beta-hydroxysterol delta24-reductase on the surface of hepatitis C virus-related hepatocellular carcinoma cells can be a target for molecular targeting therapy (2015)
  • Author(s): M. Saito, T. Takano, T. Nishimura, M. Kohara, K. Tsukiyama-Kohara
  • Journal Title: PLoS ONE Volume: 10 Issue: 4 Pages: e0124197-e0124197
  • DOI: 10.1371/journal.pone.0124197
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Protective effect of cytotoxic T lymphocytes targeting HTLV-1 bZIP factor. (2015)
  • Author(s): Sugata K, Yasunaga JI, Mitobe Y, Miura M, Miyazato P, Kohara M, and Matsuoka M.
  • Journal Title: Blood Volume: 126 Issue: 9 Pages: 1095-1105
  • DOI: 10.1182/blood-2015-04-641118
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Protective effect of influenza vaccine based on highly attenuated vaccinia virus vector (2018)
  • Author(s): Fumihiko Yasui, Keisuke Munekata, Tomoko Honda, Yasui Itoh, Yoshihiro Sakoda, Nobuo Sakaguchi, Kazumasa Ogasawara, Michinori Kohara
  • Organizer: The 12 th China-Japan International Conference of Virology
  • Int'l Joint Research
• [Presentation] Evaluation of vaccine potential of recombinant vaccinia virus encoding H5 subtype hemagglutinin against H5N1 influena virus (2018)
  • Author(s): F.Yasui, K.Munekata, T.Fujiyuki, T.Karaishi, T.Honda, Y.Sakoda, M.Yoneda, H.Kida, C.Kai, M.kohara
  • Organizer: 12th Vaccine Congress
  • Int'l Joint Research
• [Presentation] Essential Role for Serial Immune responses in Protection against Influenza H5N1 in Mice by an Attenuated Vaccinia Virus Vector Expressing Influenza Virus H5 HA (2018)
  • Author(s): Tomoko Honda, keisuke Munekata, Fumihiko Yasui, Kenzaburou Yamaji, Nobuo Sakaguchi, Michinori Kohara
  • Organizer: 12th Vaccine Congress
  • Int'l Joint Research
• [Presentation] Elucidation of mechanism undergoing elimination of HPAI H5N1 virus in mice vaccinated with recombinant H5 vaccine based on vaccinia virus vector (2017)
  • 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
  • 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
• [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
• [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
• [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
• [Presentation] Amelioration of HCV liver fibrosis by selective inhibitor of Wnt/β-catenin/CBP signaling (2016)
  • Author(s): Tokunaga Y., Osawa Y., Ohtsuki K., Yamaji K., Yamane D., Munekata K., Hara M., Kojima S., Kimura K., Kohara M.
  • Organizer: 23rd International Symposium on Hepatitis C Virus and Related Viruses
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2016-10-11
  • Int'l Joint Research
• [Presentation] Transcriptome profiling reveals quick immune response in the early stage of HBV infection in Tupaia belangeri (2016)
  • Author(s): Sanada T.,Tsukiyama-Kohara K., Yamamoto N., Kayesh MEH., Takano J., Shiogama Y., Yasutomi Y., Kohara M.
  • Organizer: International Meeting on Molecular Biology of Hepatitis B Viruses
  • Place of Presentation: ソウル（韓国）
  • Year and Date: 2016-09-21
  • Int'l Joint Research
• [Presentation] Prevention effect of H5N1 HPAI and H1N1 pdm2009 influenza vaccine based on highly attenuated vaccinia virus vector in cynomolgus monkeys (2016)
  • 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
  • Int'l Joint Research
• [Presentation] Heterologous vaccination with DNA vaccine and recombinant vaccinia virus carrying the cDNA of HCV induced effective immunity in mouse model (2015)
  • Author(s): Yumiko Shiomaga, Michinori Kohara, Yasuhiro Yasutomi
  • 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
• [Presentation] Highly pathogenic avian influenza A H5N1 virus causes severe symptoms due to insufficient interaction of dendritic cells with T cells (2015)
  • 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
• [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): 池尻 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
• [Presentation] DHCR24 on the surface of HCV-related hepatocellular carcinoma cells can be a target for molecular targeting therapy (2015)
  • Author(s): Makoto Saito, Takashi Takano, Tomohiro Nishimura, Michinori Kohara, Kyoko Tsukiyama-Kohara
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場（愛知県・名古屋市）
  • Year and Date: 2015-10-08
• [Presentation] Highly pathogenic avian influenza virus (H5N1) causes severe symptoms due to insufficient induction of humoral immune responses (2015)
  • 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
  • Int'l Joint Research
• [Remarks] 公益財団法人東京都医学総合研究所 感染制御プロジェクト
  • URL: http://www.igakuken.or.jp/project/detail/infectious.html
• [Remarks] 東京都医学総合研究所
  • URL: http://www.igakuken.or.jp