Influenza viral hemagglutinin-targeted macrocyclic peptides as an antiviral agent

• Project/Area Number: 25670224
• 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)
• Co-Investigator(Renkei-kenkyūsha): YASUI Fumihiko 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, 主席研究員 (40399473) ; MUNAKATA Tubasa 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, 主席研究員 (50420237) ; SAITO Makoto 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) ; MUNEKATA Keisuke 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 (30569140) ; SUGA Hiroaki 東京大学, 大学院理学系研究科, 教授 (00361668)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: インフルエンザ / 特殊環状ペプチド / 感染阻害 / インフルエンザウイルス / HA蛋白質 / 抗ウイルス剤 / パントロピック / 増殖阻害

Outline of Final Research Achievements

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 (Random non-standard Peptide Integrated Discovery) system. After five rounds selection of H5N1 HA-binding peptides, we found a total of 24 candidates for inhibitor HA (iHA).
iHA inhibited plaque formation against different clade H5N1 viruses, A/whooper swan/Mongolia/3/05 (H5N1/Mongolia; clade 2.2) and A/whooper swan/Hokkaido/1/08 (H5N1/Hokkaido; clade 2.3). Intriguingly, iHA was effective against pandemic (H1N1) 2009 viruses more than zanamivir. These results suggest that iHA is able to inhibit replication of a wide range of H1 and H5 influenza viruses via a mechanism of its interaction with HA. Polykaryon formation mediated by various clade H5 HAs were also inhibited by iHA in a dose-dependent manner.

Research Products

• [Journal Article] Phagocytic cells contribute to the antibody-mediated elimination of pulmonary-infected SARS coronavirus. (2014)
  • Author(s): Yasui F, Kohara M, Kitabatake M, Nishiwaki T, Fujii H, Tateno C, Yoneda M, Morita K, Matsushima K, Koyasu S, Kai C
  • Journal Title: Virology Volume: 454-455 Pages: 157-168
  • DOI: 10.1016/j.virol.2014.02.005
  • Peer Reviewed / Open Access
• [Journal Article] Tupaia belangeri as an experimental animal model for viral infection (2014)
  • Author(s): Kyoko Tsukiyama-Kohara, Michinori Kohara
  • Journal Title: Experimental Animals Volume: 63 Pages: 367-374
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Histopathological evaluation of the diversity of cells susceptible to H5N1 virulent avian influenza virus (2013)
  • Author(s): Ogiwara H, Yasui F, Munekata K, Takagi-Kamiya A, Munakata T, Nomura N, Shibasaki F, Kuwahara K, Sakaguchi N, Sakoda Y, Kida H, Kohara M
  • Journal Title: Am. J. Pathol Volume: 184 Issue: 1 Pages: 171-183
  • DOI: 10.1016/j.ajpath.2013.10.004
  • Peer Reviewed / Open Access
• [Journal Article] Broad-spectrum detection of h5 subtype influenza a viruses with a new fluorescent immunochromatography system (2013)
  • Author(s): Sakurai A, Takayama K, Nomura N, Munakata T, Yamamoto N, Tamura T, Yamada J, Hashimoto M, Kuwahara K, Sakoda Y, Suda Y, Kobayashi Y, Sakaguchi N, Kida H, Kohara M, Shibasaki F
  • Journal Title: PLoS One Volume: 8 Issue: 11 Pages: e76753-e76753
  • DOI: 10.1371/journal.pone.0076753
  • Peer Reviewed
• [Journal Article] Experimental Infection of Macaques with a Wild Water Bird-Derived Highly Pathogenic Avian Influenza Virus (H5N1). (2013)
  • Author(s): Fujiyuki, T., Yoneda, M., Yasui, F., Kuraishi, T., Hattori, S., Kwon, HJ., Munekata, K., Kiso, Y., Kida, H., Kohara, M., Kai, C.
  • Journal Title: PLoS One Volume: 18;8(12) Issue: 12 Pages: e83551-e83551
  • DOI: 10.1371/journal.pone.0083551
  • Peer Reviewed
• [Presentation] Highly pathogenic avian influenza A H5N1 virus causes severe symptoms due to insufficient induction of humoral immune response (2014)
  • Author(s): Ai Ikejiri, Fumihiko Yasui, Yasushi Itoh, Masahiro Kitabatake, Nobuo Sakaguchi, Kazumasa Ogasawara, Michinori Kohara
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 京都国際会館（京都）
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] H5N1高病原性鳥インフルエンザウイルス感染に対する哺乳動物宿主の免疫応答とインフルエンザ組換え生ワクチン接種による発症防御 (2014)
  • Author(s): 安井文彦、伊藤 靖、池尻 藍、北畠正大、宗方圭祐、迫田義博、喜田 宏、坂口薫雄、小笠原一誠、小原道法
  • Organizer: 第18回日本ワクチン学会学術集会
  • Place of Presentation: 福岡国際会議場（福岡）
  • Year and Date: 2014-12-06 – 2014-12-07
• [Presentation] H5N1高病原性鳥インフルエンザ組換えワクシニアワクチン単回接種による免疫長期持続作用機序の解析 (2014)
  • Author(s): 安井文彦、宗方圭祐、倉石 武、服部正策、藤幸知子、米田美佐子、迫田義博、喜田 宏、甲斐智恵子、小原道法
  • Organizer: 第62回日本ウイルス学会学術集会
  • Place of Presentation: パシフィコ横浜（神奈川）
  • Year and Date: 2014-11-10 – 2014-11-12
• [Presentation] 亜型を超えた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 (2014)
  • Author(s): 斉藤 誠、安井文彦、棟方 翼、飛田良美、小澤 真、小原恭子、伊東利紗、菅 裕明、佐々木 亨、窪田規一、小原道法
  • Organizer: 第62回日本ウイルス学会学術集会
  • Place of Presentation: パシフィコ横浜（神奈川）
  • Year and Date: 2014-11-10 – 2014-11-12
• [Presentation] Prophylatic effect of H5N1 influenza vaccine based on vaccinia virus vector in cynomolgus monkeys (2014)
  • Author(s): Fumihiko Yasui, Keisuke Munekata, Yasushi Itoh, Tomoko Fujiyuki, Takeshi Kuraishi, Yoshihiro Sakoda, Misako Yoneda, Hiroshi Kida, Shosaku Hattori, Chieko Kai, Kazumasa Ogasawara, Michinori Kohara
  • Organizer: 8th Vaccine & ISV Congress
  • Place of Presentation: Philadelphia (USA)
  • Year and Date: 2014-10-26 – 2014-10-28
• [Presentation] Prophylatic effect of H5N1 influenza vaccine based on attenuated replicative vaccinia virus that contains endogenous adjuvant component (2014)
  • Author(s): Fumihiko Yasui, Keisuke Munekata, Yasushi Itoh, Tomoko Fujiyuki, Takeshi Kuraishi, Yoshihiro Sakoda, Misako Yoneda, Hiroshi Kida, Shosaku Hattori, Chieko Kai, Kazumasa Ogasawara, Michinori Kohara
  • Organizer: KeystoneSymposia
  • Place of Presentation: Seattle (USA)
  • Year and Date: 2014-10-08 – 2014-10-13
• [Presentation] 霊長類感染モデルを用いた高病原性鳥インフルエンザウイルス抗原発現組換え麻疹ウイルスの防御効果の解析 (2014)
  • Author(s): 藤幸知子、堀江 亮、米田美佐子、倉石 武、安井文彦、宗片圭祐、池田房子、基礎友里、権賢 貞、石井美穂、佐藤宏樹、服部正策、喜田 宏、小原道法、甲斐知恵
  • Organizer: 第61回日本実験動物学会
  • Place of Presentation: 札幌コンベンションセンター（札幌）
  • Year and Date: 2014-05-15 – 2014-05-17
• [Remarks] 公益財団法人東京都医学総合研究所プロジェクト研究
  • URL: http://www.igakuken.or.jp/project/detail/infectious.html