Influenza viral hemagglutinin-targeted macrocycles as an antiviral agent

2012 Fiscal Year Final Research Report

• Project/Area Number: 23659238
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Virology
• Research Institution: 公益財団法人東京都医学総合研究所 (2012); Tokyo Metropolitan Organization for Medical Research (2011)
• 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, プロジェクトリーダー (10250218)
• Co-Investigator(Renkei-kenkyūsha): 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) ; 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) ; 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)
• Project Period (FY): 2011 – 2012
• Keywords: 感染防御 / ワクチン / 特殊環状ペプチド

Research Abstract

We identified macrocyclic peptides that bind the viral envelope protein hemagglutinin (HA) of influenza A viruses and inhibit its biological function by using the Random non-standard Peptide Integrated Discovery (RaPID) system. The macrocycles inhibited virus replication and exhibited efficacy against viral pneumonia in a mouse model. These results indicate that the RaPID system allows for the development of a new class of HA-targeted antivirals for influenza treatment.

Research Products

• [Journal Article] Targeted induction of interferon-λ in humanized chimeric mouse liver abrogates hepatotropic virus infection (2013)
  • Author(s): Shin-ichiro Nakagawa, Yuichi Hirata, Takeshi Kameyama, Yuko Tokunaga, Yasumasa Nishito, Kazuko Hirabayashi, Junichi Yano, Takahiro Ochiya, Chise Tateno, Yasuhito Tanaka, Masashi Mizokami, Kyoko Tsukiyama-Kohara, Kazuaki Inoue, Makoto Yoshiba, Akinori Takaoka and Michinori Kohara
  • Journal Title: PLoSONE Volume: 8(3) Pages: e59611
  • Peer Reviewed
• [Journal Article] Synthetic lipophilic antioxidant BO-653 suppresses HCV replication (2013)
  • Author(s): Fumihiko Yasui, Masayuki Sudoh, Masaaki Arai, Michinori Kohara
  • Journal Title: J. Med. Virol. J. Med. Virol Volume: 85(2) Pages: 241-9
  • Peer Reviewed
• [Journal Article] Hepatitis C virus kinetics by administration of pegylated interferon-α in human and chimeric mice carrying human hepatocytes with variants of the IL28B gene (2012)
  • Author(s): Tsunamasa Watanabe, Fuminaka Sugauchi, Yasuhito Tanaka, Kentaro Matsuura, Hiroshi Yatsuhashi, Shuko Murakami, Sayuki Iijima, Etsuko Iio, Masaya Sugiyama, Takashi Shimada, Masakazu Kakuni, Michinori Kohara, Masashi Mizokami
  • Journal Title: Gut Volume: (in press)
  • Peer Reviewed
• [Journal Article] Immunization with a recombinant vaccinia virus that encodes nonstructural proteins of the hepatitis C virus suppresses viral protein levels in mouse liver (2012)
  • Author(s): Satoshi Sekiguchi, Kiminori Kimura, Tomoko Chiyo, Takahiro Ohtsuki, Yoshimi Tobita, Yuko Tokunaga, Fumihiko Yasui, Kyoko Tsukiyama-Kohara, Takaji Wakita, Toshiyuki Tanaka, Masayuki Miyasaka, Kyosuke Mizuno, Yukiko Hayashi, Tsunekazu Hishima, Kouji Matsushima and Michinori Kohara
  • Journal Title: PLoS ONE Volume: 7(12) Pages: e51656
  • Peer Reviewed
• [Journal Article] Impairment of interferon regulatory factor-1 3 activation by hepatitis C virus core protein basic region 1 (2012)
  • Author(s): Kazuaki Inoue, Kyoko Tsukiyama-Kohara, Chiho Matsuda1, Mitsutoshi Yoneyama, Takashi Fujita, Shusuke Kuge, Makoto Yoshiba and Michinori Kohara
  • Journal Title: Biochem Biophys Res Commun Volume: 428(4) Pages: 494-499
  • Peer Reviewed
• [Journal Article] Self-enhancement of Hepatitis C Virus Replication by Promotion of Specific Sphingolipid Biosynthesis (2012)
  • Author(s): Yuichi Hirata, Kazutaka Ikeda, Masayuki Sudoh, Akemi Suzuki, Yuko Tokunaga, Leiyun Weng, Masatoshi Ohta, Yoshimi Tobita, Ken Okano, Kazuhisa Ozeki, Kenichi Kawasaki, Takuo Tsukuda, Asao Katsume, Yuko Aoki, Takuya Umehara, Satoshi Sekiguchi, Tetsuya Toyoda, Kunitada Shimotohno, Tomoyoshi Soga, Masahiro Nishijima, Ryo Taguchi, and Michinori Kohara
  • Journal Title: PLoS Pathog Volume: 8(8) Pages: e1002860
  • Peer Reviewed
• [Journal Article] PA from an H5N1 highly pathogenic avian influenza virus activates viral transcription and replication, and induces apoptosis and interferon expression (2012)
  • Author(s): Qiang Wang, Shijian Zhang, Hongbing Jiang, Jinalan Wang, Leiyun, Weng, Yingying Mao, Satoshi Sekiguchi, Fumihiko Yasui, Michinori Kohara, Philippe Buchy, Vincent Deubel, Ke Xu, Bing Sun and Tetsuya Toyoda
  • Journal Title: Virology Journal Volume: 8;9 Pages: 106-118
  • Peer Reviewed
• [Journal Article] An orally available, small-molecule interferon inhibits hepatitis C virus replication (2012)
  • Author(s): Hideyuki Konishi, Koichi Okamoto, Yusuke Ohmori, Hitoshi Yoshino, Hiroshi Ohmori, Motooki Ashiara, Yuichi Hirata, Atsunori Ohta, Hiroshi Sakamoto, Natsuko Hada, Asao Katsume, Michinori Kohara, Kazumi Morikawa, Takuo Tsukuda, Nobuo Shimma, Graham Foster, William Alazawi, Yuko Aoki, Mikio Arisawa, and Masayuki Sudoh
  • Journal Title: Sci. Comm Volume: 2 Pages: 259
  • Peer Reviewed
• [Journal Article] Detergent-induced activation of the hepatitis C virus genotype 1b RNA polymerase (2012)
  • Author(s): Leiyun Weng; Michinori Kohara; Takaji Wakita; Kunitada Shimotohno; Tetsuya Toyoda
  • Journal Title: Gene Volume: 496 Pages: 79-87
  • Peer Reviewed
• [Journal Article] Hepatitis C virus induces overexpression of 3.-hydroxysterol .24-reductase through Sp1 (2012)
  • Author(s): Makoto Saito, Michinori Kohara, Yuri Kasama and Kyoko Tsukiyama-Kohara
  • Journal Title: J. Med. Virol Volume: 84 Pages: 733-746
  • Peer Reviewed
• [Journal Article] Translocase of outer mitochondrial membrane 70 induces interferon response and is impaired by hepatitis C virus NS3 (2012)
  • Author(s): Yuri Kasama, Makoto Saito, Takashi Takano, Tomohiro Nishimura, Masaaki Satoh, Zhonzhi Wang, Nagla Elwy, Shinji Harada, Michinori Kohara, Kyoko Tsukiyama-Kohara
  • Journal Title: Virus Res Volume: 163 Pages: 405-409
  • Peer Reviewed
• [Journal Article] Monoclonal antibody 2-152a suppresses hepatitis C virus infection through betaine/GABA transporter-1 (2011)
  • Author(s): Masaaki Satoh, Makoto Saito, Takashi Takano, Yuri Kasama, Tomohiro Nishimura, Yasumasa Nishito, Yuichi Hirata, Masaaki Arai, Masayuki Sudo, Chieko Kai, Michinori Kohara, and Kyoko Tsukiyama-Kohara
  • Journal Title: J Infect Dis Volume: 204(8) Pages: 1172-80
  • Peer Reviewed
• [Journal Article] Conditional hepatitis C virus gene expression without induction of severe inflammatory responses through the use of a Cre-expressing recombinant adenovirus in mice (2011)
  • Author(s): Tomoko Chiyo, Satoshi Sekiguchi, Masahiro Hayashi, Yoshimi Tobita, Yumi Kanegae, Izumu Saito, and Michinori Kohara
  • Journal Title: Virus Res Volume: 160(1-2) Pages: 89-97
  • Peer Reviewed
• [Journal Article] Augmentation of DHCR24 expression by hepatitis C virus infection facilitates viral replication in hepatocytes (2011)
  • Author(s): Takashi Takano, Kyoko Tsukiyama-Kohara, Masahiro Hayashi, Yuichi Hirata, Masaaki Satoh, Chise Tateno, Yukiko Hayashi, Tsunekazu Hishima, Nobuaki Funata, Masayuki Sudo, and Michinori Kohara
  • Journal Title: J. Hepatology Volume: 55(3) Pages: 512-21
  • Peer Reviewed
• [Journal Article] Frontiers of Model Animals for Human Diseases (2011)
  • Author(s): Kiminori Kimura, Michinori Kohara
  • Journal Title: Experimental Animals Volume: 60(2) Pages: 93-100
  • Peer Reviewed
• [Journal Article] Translocase of outer mitochondrial membrane 70 is induced by hepatitis C virus and is related to the apoptotic response (2011)
  • Author(s): Takashi Takano, Michinori Kohara, Yuri Kasama, Tomohiro Nishimura, Makoto Saito, Chieko Kai, and Kyoko Tsukiyama-Kohara
  • Journal Title: J. Med. Virol Volume: 83 Pages: 801-809
  • Peer Reviewed
• [Journal Article] Role of interleukin-18 in intrahepatic inflammatory cell recruitment in acute liver injury (2011)
  • Author(s): Kiminori kimura, Satoshi Sekiguchi, Seishu Hayashi, Yukiko Hayashi, Tsunekazu Hishima, Masahito Nagaki, and Michinori Kohara
  • Journal Title: Journal of Leukocyte Biology Volume: 89 Pages: 433-442
  • Peer Reviewed
• [Journal Article] Establishment of infectious HCV virion-producing cells with newly designed full-genome replicon RNA (2011)
  • Author(s): Masaaki Arai, Hidenori Suzuki, Yoshimi Tobita, Asako Takagi, Koichi Okamoto, Atsunori Ohta, Masayuki Sudoh, Kunitada Shimotohno, Michinori Kohara
  • Journal Title: Arch. Virol Volume: 156 Pages: 295-304
  • Peer Reviewed
• [Presentation] Immunization with a recombinant vaccinia virus encoding a nonstructural protein of the hepatitis C virus ameliorates chronic hepatitis in the liver of transgenic mice (2012)
  • Author(s): Kimura K., Sekiguchi S., Otsuki T., Tokunaga Y., Kohara M
  • Organizer: Keystone Symposia on Molecular and Cellular Biology
  • Place of Presentation: Ottawa (Canada)
  • Year and Date: 20121213-18
• [Presentation] Self-enhancement of hepatitis C Virus replication by promotion of specific sphingolipid biosynthesis (2012)
  • Author(s): Hirata Y., Ikeda K., Sudoh M., Tokunaga Y., Tobita Y., Taguchi R., Kohara M
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡国際会議場(福岡)
  • Year and Date: 20121211-14
• [Presentation] Single immunization with H5N1 influenza vaccine based on recombinant vaccinia virus protects mice and macaques from challenge with H5N1 influenza virus (2012)
  • Author(s): Yasui F., Munekata K., Itoh Y., Sakoda Y., Kida H., Ogasawara K., Kohara M
  • Organizer: 第41回日本免疫学会学術集会
  • Place of Presentation: 神戸国
  • Year and Date: 20121205-17
• [Presentation] HCV感染による慢性肝炎の病態形成と治療ワクチン (2012)
  • Author(s): 小原道法、大槻貴博、徳永優子、木村公則
  • Organizer: 第16回日本ワクチン学会学術集会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 20121117-18
• [Presentation] 新世代抗体医薬としての特殊環状ペプチドによるインフルエンザウイルス増殖阻害効果 (2012)
  • Author(s): 斉藤 誠、飛田良美、棟方 翼、伊藤利紗、菅 裕明、佐々木 亨、窪田規一、小澤 真、小原恭子、小原道法
  • Organizer: 第60回日本ウイルス学会学術集会
  • Place of Presentation: グランキューブ大阪(大阪)
  • Year and Date: 20121113-05
• [Presentation] C型肝炎ウイルスによるスフィンゴ脂質の合成促進とウイルス複製環境の構築 (2012)
  • Author(s): 平田雄一、池田和貴、須藤正幸、徳永優子、田口 良、小原道法
  • Organizer: 第60回日本ウイルス学会学術集会
  • Place of Presentation: グランキューブ大阪(大阪)
  • Year and Date: 20121113-05
• [Presentation] Development of recombinant H5N1 influenza vaccine based on vaccinia virus vector (2012)
  • Author(s): Yasui F., Sakoda Y., Kida H., Itoh Y., Ogasawara K., Kohara M
  • Organizer: 6^<th> Vaccine & ISV Congress
  • Place of Presentation: Shanghai(China)
  • Year and Date: 20121014-16
• [Presentation] Interferon-lambda plays a critical role in antiviral response in human hepatocytes (2011)
  • Author(s): Hirata Y., Kameyama T., Tokunaga Y., Nakagawa S., Hayashi Y., Takaoka A., Kohara M
  • Organizer: 第34回日本分子生物学会
  • Place of Presentation: 横浜
  • Year and Date: 20111213-16
• [Presentation] H5N1高病原性鳥インフルエンザウイルスHA発現組換えワクシニアウイルスワクチンによる発症防御機序の解析 (2011)
  • Author(s): 宗片圭祐、安井文彦、迫田義博、喜田 宏、柴田伸一、村上利夫、小原道法
  • Organizer: 第15回日本ワクチン学会
  • Place of Presentation: 東京
  • Year and Date: 20111210-11
• [Presentation] Recombinant vaccinia virus encoding hepatitis C virus nonstructural protein modulates host immune response and ameliorates chronic hepatitis in mouse model (2011)
  • Author(s): Kimura K., Otsuki T., Kohara M
  • Organizer: 第40回日本免疫学会学術集会
  • Place of Presentation: 千葉
  • Year and Date: 20111127-29
• [Presentation] Recombinant vaccinia virus encoding hepatitis C virus nonstructural protein modulates host immune response and ameliorates chronic hepatitis in mouse model (2011)
  • Author(s): Kimura K., Otsuki T., Kohara M
  • Organizer: The American Association for the Study of Liver Diseases
  • Place of Presentation: San Francisco
  • Year and Date: 20111104-18
• [Presentation] Suppression of sphingomyelin augmented by hepatitis C virus has robust anti-viral effects in human livers (2011)
  • Author(s): Hirata Y., Ikeda K., Sudoh M., Tokunaga Y., Tobita Y., Taguchi R., Kohara M
  • Organizer: The American Association for the Study of Liver Diseases
  • Place of Presentation: San Francisco
  • Year and Date: 20111104-08
• [Presentation] C型肝炎ウイルスの複製におけるDHCR24の役割 (2011)
  • Author(s): 高野貴士、小原道法、小原恭子
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 20111003-05
• [Presentation] C型肝炎発症におけるウイルス蛋白質と炎症性サイトカイン (2011)
  • Author(s): 小道道法、木村公則、小原恭子
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 20111003-05
• [Presentation] A single immunization with highly attenuated vaccinia virus DIs-based vaccines induce protective immunity against H5N1 avian influenza virus in mice (2011)
  • Author(s): Gomi S., Naganawa S., Yasui F., Munekata K., Ishii K., Sakoda Y., Kida H. Kohara M
  • Organizer: International Union of Microbiological Societies(IUMS)2011
  • Place of Presentation: Sapporo
  • Year and Date: 20110911-16
• [Presentation] Suppression of sphingomyelin augmented by hepatitis C virus has robust anti-viral effects in human livers (2011)
  • Author(s): Hirata Y., Ikeda K., Sudoh M., Tokunaga Y., Tobita Y., Taguchi R., Kohara M
  • Organizer: International Union of Microbiological Societies(IUMS)2011
  • Place of Presentation: Sapporo
  • Year and Date: 20110911-16
• [Presentation] Clearance of SARS-CoV by cooperation of antibodies and phagocytes (2011)
  • Author(s): Yasui F., Kai C., Morita K., Kohara M
  • Organizer: International Union of Microbiological Societies(IUMS)2011
  • Place of Presentation: Sapporo
  • Year and Date: 20110911-16
• [Presentation] Spontaneous development of B-cell lymphomas by persistent expression of the full genome of hepatitis C virus in B cells in mics (2011)
  • Author(s): Tsukiyama-Kohara K., Kohara M
  • Organizer: 2011 ASBMB Special Symposia Series
  • Place of Presentation: Guangzhou China
  • Year and Date: 20110724-26
• [Presentation] PCRとin situ hybridizationを組み合わせたHCVとHBVのウイルスゲノム存在様式可視化の試み (2011)
  • Author(s): 井上和明、塗谷秀子、小原道法
  • Organizer: 第47回日本肝臓学会総会
  • Place of Presentation: 東京
  • Year and Date: 20110602-03
• [Presentation] HCV感染による慢性肝炎の病態形成と炎症性サイトカインの関与 (2011)
  • Author(s): 木村公則、小原道法
  • Organizer: 第47回日本肝臓学会総会
  • Place of Presentation: 東京
  • Year and Date: 20110602-03
• [Presentation] 新規C型慢性肝炎モデルマウスを用いたC型慢性肝炎の病態解析 (2011)
  • Author(s): 大槻貴博、関口 敏、飛田良美、木村公則、小原道法
  • Organizer: 第58回日本実験動物学会総会
  • Place of Presentation: 東京
  • Year and Date: 20110525-27
• [Presentation] Immunization with recombinant vaccinia virus expressing hemagglition protein of H5N1 HPAIV protect mice from lethal H5N1 HPIV infection via the nentralizing antibody-independent mechanism (2011)
  • Author(s): Yasui F., Munekata K., Sakoda Y., Kida H., Shibata S., Murakami T., Kohara M
  • Organizer: Keystone Symposia-Pathogenesis of Influenza
  • Place of Presentation: Kowloon (Hong Kong)
  • Year and Date: 20110523-28
• [Book] 肝炎ウイルスモデル〈series モデル動物利用マニュアル〉疾患モデルの作成と利用-がん 第3章 消化器系 第2節 肝臓 第3章 肝炎ウイルスモデル (2012)
  • Author(s): 小原道法、木村公則、小原恭子
  • Total Pages: 346-358
• [Book] CV治療ワクチンの開発についてがんと化学療法 (2012)
  • Author(s): 木村公則、小原道法
  • Total Pages: 1451-1457
• [Book] C型肝炎ウイルス感染モデル〈series モデル動物利用マニュアル〉疾患モデルの作成と利用-糖尿病・肥満/感染症 第II部 感染症 (2012)
  • Author(s): 小原道法、木村公則、小原恭子
  • Total Pages: 188-197
• [Book] 「ヒト肝細胞における強力なIFN-λ誘導による抗ウイルス効果」 消化器内科 55(2) (2012)
  • Author(s): 平田雄一、小原道法
  • Total Pages: 271-277
• [Book] 細胞膜成分を標的としたC型肝炎治療薬 BIO Clinica 26(8) (2011)
  • Author(s): 須藤正幸、小原道法
  • Total Pages: 920-924
• [Book] C型肝炎ウイルスによる免疫攪乱と炎症発がん BIO Clinica 26(10) (2011)
  • Author(s): 小原恭子、小原道法
  • Total Pages: 904-910
• [Book] 新時代のウイルス性肝炎学.「HCVの病原性発現に関与するウイルス因子とその機能 日本臨床 69巻増刊号4 (2011)
  • Author(s): 小原恭子、棟方 翼、小原道法
• [Remarks]
  • URL: http://www.igakuken.or.jp/
• [Patent(Industrial Property Rights)] 抗インフルエンザウイルス活性を有するペプチド (2011)
  • Inventor(s): 小原道法、佐々木 亨、パトリック・リード
  • Industrial Property Rights Holder: ぺプチドリーム株式会社、財団法人東京都医学総合研究所
  • Industrial Property Number: 特許、特願2011-211100
  • Filing Date: 2011-09-27