Development of anti-hepatitis virus strategy based on proteomics

• Project/Area Number: 15K08493
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Virology
• Research Institution: University of Yamanashi
• Principal Investigator: MORIISHI Kohji 山梨大学, 大学院総合研究部, 教授 (90260273)
• Co-Investigator(Renkei-kenkyūsha): YAMASHITA Atsuya 山梨大学, 大学院総合研究部, 助教 (00334871) ; KASAI Hirotake 山梨大学, 大学院総合研究部, 助教 (20324189) ; TANAKA Tomohisa 山梨大学, 大学院総合研究部, 助教 (30585310)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: HCV / C型肝炎 / HBV / B型肝炎 / 抗ウイルス剤 / 宿主蛋白質 / 宿主因子 / 抗ウイルス化合物

Outline of Final Research Achievements

The aim of this study was identification of antiviral compounds that targeted host agents interacting proteins of hepatitis B and C viruses (HBV and HCV) based on proteomics information. FKBP6 and HM13 were identified as essential host proteins for HCV replication and the viral particle production and its pathogenicity. DM-CHX and cinnamic acid derivatives, which target them, prevented HCV replication and production. Furthermore, pTEFb inhibitor could suppress HBV replication and production. These results will contribute to development of novel antiviral agents targeting production and pathogenicity of HBV and HCV

Research Products

• [Journal Article] Roles of the 5' Untranslated Region of Nonprimate Hepacivirus in Translation Initiation and Viral Replication. (2018)
  • Author(s): Tanaka T, Otoguro T, Yamashita A, Kasai H, Fukuhara T, Matsuura Y, Moriishi K.
  • Journal Title: Journal of Virology Volume: 92 Issue: 7
  • DOI: 10.1128/jvi.01997-17
  • Peer Reviewed
• [Journal Article] Cinnamic acid derivatives inhibit hepatitis C virus replication via the induction of oxidative stress. (2017)
  • Author(s): Amano R, Yamashita A, Kasai H, Hori T, Miyasato S, Saito S, Yokoe H, Takahashi K, Tanaka T, Otoguro T, Maekawa S, Enomoto N, Tsubuki M, Moriishi K.
  • Journal Title: Antiviral Research Volume: 145 Pages: 123-130
  • DOI: 10.1016/j.antiviral.2017.07.018
  • Peer Reviewed / Open Access
• [Journal Article] The potential of signal peptide peptidase as a therapeutic target for hepatitis C. (2017)
  • Author(s): Moriishi K
  • Journal Title: Current Opinions on Therapeutic Targets Volume: 21 Issue: 9 Pages: 827-836
  • DOI: 10.1080/14728222.2017.1369959
  • Peer Reviewed
• [Journal Article] Hepatocyte Factor JMJD5 Regulates Hepatitis B Virus Replication through Interaction with HBx (2016)
  • Author(s): Kouwaki T, Okamoto T, Ito A, Sugiyama Y, Yamashita K, Suzuki T, Kusakabe S, Hirano J, Fukuhara T, Yamashita A, Saito K, Okuzaki D, Watashi K, Sugiyama M, Yoshio S, Standley DM, Kanto T, Mizokami M, Moriishi K, Matsuura Y
  • Journal Title: J Virol Volume: 90 Issue: 7 Pages: 3530-3542
  • DOI: 10.1128/jvi.02776-15
  • Peer Reviewed
• [Journal Article] Inhibitory effect of CDK9 inhibitor FIT-039 on hepatitis B virus propagation (2016)
  • Author(s): T. Tanaka, K. Okuyama-Dobashi, S. Murakami, W. Chen, T. Okamoto, K. Ueda, T. Hosoya, Y. Matsuura, A. Ryo, Y. Tanaka, M. Hagiwara and K. Moriishi
  • Journal Title: Antiviral Research Volume: 133 Pages: 156164-156164
  • DOI: 10.1016/j.antiviral.2016.08.008
  • Peer Reviewed
• [Journal Article] Inhibitory effect of presenilin inhibitor LY411575 on maturation of hepatitis C virus core protein, production of the viral particle and expression of host proteins involved in pathogenicity. (2016)
  • Author(s): Otoguro T, Tanaka T, Kasai H, Yamashita A, Moriishi K.
  • Journal Title: Microbiol Immunol. Volume: 60 Issue: 11 Pages: 740-753
  • DOI: 10.1111/1348-0421.12448
  • NAID: 40021031203
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Involvement of FKBP6 in hepatitis C virus replication. (2015)
  • Author(s): Kasai H, Kawakami Y, Yokoe H, Yoshimura K, Matsuda M, Yasumoto J, Maekawa S, Yamashita A, Tanaka T, Ikeda M, Kato N, Okamoto T, Matsuura Y, Sakamoto N, Enomoto N, Takeda S, Fujii H, Tsubuki M, Kusunoki M, Moriishi K.
  • Journal Title: Scientific reports Volume: 5 Issue: 1 Pages: 16699-16699
  • DOI: 10.1038/srep16699
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Identification of antiviral agents targeting hepatitis B virus promoter from extracts of Indonesian marine organisms by a novel cell-based screening assay. (2015)
  • Author(s): Yamashita A, Fujimoto Y, Tamaki M, Setiawan A, Tanaka T, Okuyama-Dobashi K, Kasai H, Watashi K, Wakita T, Toyama M, Baba M, de Voogd NJ, Maekawa S, Enomoto N, Tanaka J, Moriishi K
  • Journal Title: Marine Drug Volume: 13 Issue: 11 Pages: 6759-6773
  • DOI: 10.3390/md13116759
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Hepatitis B virus efficiently infects non-adherent hepatoma cells via human sodium taurocholate cotransporting polypeptide. (2015)
  • Author(s): Okuyama-Dobashi K, Kasai H, Tanaka T, Yamashita A, Yasumoto J, Chen W, Okamoto T, Maekawa S, Watashi K, Wakita T, Ryo A, Suzuki T, Matsuura Y, Enomoto N, Moriishi K.
  • Journal Title: Scientific reports Volume: 5 Issue: 1 Pages: 17047-17047
  • DOI: 10.1038/srep17047
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Deep sequencing and phylogenetic analysis of variants resistant to interferon-based protease inhibitor therapy in chronic hepatitis induced by genotype 1b hepatitis C virus. (2015)
  • Author(s): Sato M, Maekawa S, Komatsu N, Tatsumi A, Miura M, Muraoka M, Suzuki Y, Amemiya F, Takano S, Fukasawa M, Nakayama Y, Yamaguchi T, Uetake T, Inoue T, Sato T, Sakamoto M, Yamashita A, Moriishi K, Enomoto N.
  • Journal Title: J Virol Volume: 89(11) Issue: 11 Pages: 6105-16
  • DOI: 10.1128/jvi.03127-14
  • Peer Reviewed / Open Access
• [Journal Article] Novel sex-dependent differentially methylated regions are demethylated in adult male mouse livers (2015)
  • Author(s): Ito S, Hirabayashi K, Moriishi K, Matsui Y, Moriya K, Koike K, Matsuura Y, Shiota K, Yagi S.
  • Journal Title: Biochem Biophys Res Commun Volume: 462 Issue: 4 Pages: 332-338
  • DOI: 10.1016/j.bbrc.2015.04.137
  • Peer Reviewed
• [Presentation] Establishment of hepatitis B and C virus co-infection cell line. (2017)
  • Author(s): Teruhime Otoguro, Tomohisa Tanaka, Hirotake Kasai, Atsuya Yamashita, Kohji Moriishi
  • Organizer: 第65回日本ウイルス学会総会
• [Presentation] Cross-species compatibility of hepacivirus 5’ untranslated region (2016)
  • Author(s): Tanaka T, Otoguro T, Kasai H, Yamashita A, Okuyama-Dobashi K, Moriishi K
  • Organizer: 第64回日本ウイルス学会総会
  • Place of Presentation: 札幌コンベンションセンター（札幌白石区）
  • Year and Date: 2016-10-23
  • Int'l Joint Research
• [Presentation] CDK9 inhibitor FIT-039 suppresses HBV propagation (2016)
  • Author(s): Moriishi K, Tanaka T, Okuyama-Dobashi K, Chen W, Okamoto T, Ueda K, Hosaya T, Matsuura Y, Ryo A, Tanaka Y, Hagiwara M
  • Organizer: 第64回日本ウイルス学会総会
  • Place of Presentation: 札幌コンベンションセンター（札幌白石区）
  • Year and Date: 2016-10-23
  • Int'l Joint Research
• [Presentation] Hepatitis C virus infection impairs mono-ubiquitination of histone H2A and activates expression of homeobox genes. (2016)
  • Author(s): Kasai H, Tanaka T, Yamashita A, Dobashi-Okuyama K, Moriishi K.
  • Organizer: 第64回日本ウイルス学会総会
  • Place of Presentation: 札幌コンベンションセンター（札幌白石区）
  • Year and Date: 2016-10-23
  • Int'l Joint Research
• [Presentation] Establishment of highly HBV-permissible HepG2 cell line to facilitate screening of antiviral compounds (2016)
  • Author(s): Otoguro T, Tanaka T, Chen W, Kasai H, Yamashita A, Okuyama-Dobashi K, Moriishi K
  • Organizer: 第64回日本ウイルス学会総会
  • Place of Presentation: 札幌コンベンションセンター（札幌白石区）
  • Year and Date: 2016-10-23
  • Int'l Joint Research
• [Presentation] Inhibition of HBV propagation by treatment with CDK9 inhibitor FIT-039 (2016)
  • Author(s): Tanaka T, Okuyama-Dobashi K, Chen W, Okamoto T, Ueda K, Hosaya T, Matsuura Y, Ryo A, Tanaka Y, Hagiwara M and Moriishi K
  • Organizer: 2016 International HBV meeting
  • Place of Presentation: ソウル、韓国
  • Year and Date: 2016-09-21
  • Int'l Joint Research
• [Presentation] Characterization of the IRES activity in equine hepacivirus 5’UTR (2015)
  • Author(s): Tomohisa Tanaka, Wenjia Chen, Teruhime Otoguro, Hirotake Kasai, Atsuya Yamashita, Kohji Moriishi
  • Organizer: 日本ウイルス学会
  • Place of Presentation: 福岡国際会議場（福岡県福岡市）
  • Year and Date: 2015-11-22
• [Presentation] Inhibitory effect of tyrphostin derivative HD-31 on hepatitis C virus replication via regulation of reactive oxygen species production. (2015)
  • Author(s): Ryota Amano, Atsuya Yamashita, Hirotake Kasai, Kohji Moriishi
  • Organizer: 日本ウイルス学会
  • Place of Presentation: 福岡国際会議場（福岡県福岡市）
  • Year and Date: 2015-11-22
• [Presentation] Metachromin A, sesquiterpene from marine sponge Dactylospongia metachromia, exerts anti-HBV activity via inhibition of HBV core promoter (2015)
  • Author(s): Atsuya Yamashita, Tomohisa Tanaka, Kaori Okuyama-Dobashi, Hirotake Kasai, Koichi Watashi, Takaji Wakita,, Masaaki Toyama, Masanori Baba, Mayumi Tamaki, Junichi Tanaka, Kohji Moriishi
  • Organizer: 日本ウイルス学会
  • Place of Presentation: 福岡国際会議場（福岡県福岡市）
  • Year and Date: 2015-11-22
• [Presentation] プレセニリン阻害剤のC型肝炎ウイルス増殖抑制効果の検討 (2015)
  • Author(s): 乙黒光姫、田中智久、葛西宏威、山下篤哉、森石恆司
  • Organizer: 日本ウイルス学会
  • Place of Presentation: 福岡国際会議場（福岡県福岡市）
  • Year and Date: 2015-11-22
• [Presentation] Hepatitis B virus infection impairs lipid droplet growth via host regulatory proteins (2015)
  • Author(s): Kohji Moriishi
  • Organizer: The 2015 Italy-Japan Liver Workshop
  • Place of Presentation: ナポリ大学（イタリア、ナポリ）
  • Year and Date: 2015-10-26
  • Int'l Joint Research / Invited
• [Presentation] Infection of equine hepacivirus in a closed colony of Japanese native hors（ (2015)
  • Author(s): Tomohisa Tanaka, Wenjia Chen, Teruhime Otoguro, Hirotake Kasai, Atsuya Yamashita, Kohji Moriishi
  • Organizer: 22nd International meeting on hepatitis C virus and related viruses
  • Place of Presentation: Palais de la Musique et des Congres (フランス、ストラスブール)
  • Year and Date: 2015-10-09
  • Int'l Joint Research
• [Book] Structural Proteins of HCV and Biological Functions in "Hepatitis C virus I: Cellular and Molecular Virology" (2016)
  • Author(s): Moriishi K, Matsuura Y, (Ed. by Miyamura T, Lemon SM, Walker CM, Wakita T
  • Total Pages: 23
  • Publisher: Springer
• [Remarks] 山梨大学大学院総合研究部医学域基礎医学系微生物学講座
  • URL: http://www.med.yamanashi.ac.jp/clinical_basic/microbio/Microbiology_Yamanashi_Uni_Japanese/Home.html
• [Remarks] 山梨大学大学院医学工学研究部医学学域 山梨大学医学部 微生物学講座
  • URL: http://www.med.yamanashi.ac.jp/clinical_basic/microbio/Microbiology_Yamanashi_Uni_Japanese/Home.html