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

• Project/Area Number: 15K15146
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• 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)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥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.

Research Products

• [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] 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] 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
  • Peer Reviewed / Open Access
• [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] Immature Core protein of hepatitis C virus induces an unfolded protein response through inhibition of ERAD-L in a yeast model system (2016)
  • 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
  • Peer Reviewed
• [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] 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
  • Peer Reviewed / Open Access / 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] 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
  • 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 Vivo (2015)
  • Author(s): Yusuke Sato, Hideyoshi Harashima and Michinori Kohara
  • Journal Title: Methods in Molecular Biology Volume: 7 Pages: 71-78
• [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] 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] 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] 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] 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] Efficacy of recombinant measles virus expressing highly pathogenic avian influenza virus antigen in non-human primate model (2015)
  • 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
• [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): 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] 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] 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
• [Remarks] 東京都医学総合研究所
  • URL: http://www.igakuken.or.jp