High throughput screening of chemical library for antiviral compounds for hepatitis viruses

• Project/Area Number: 24390185
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Hokkaido University
• Principal Investigator: SAKAMOTO Naoya 北海道大学, 医学(系)研究科(研究院), 教授 (10334418)
• Co-Investigator(Kenkyū-buntansha): ASAHINA Yasuhiro 東京医科歯科大学, 大学院医歯学総合研究科, 寄附講座教員 (00422692)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥17,940,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥4,140,000); Fiscal Year 2014: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000); Fiscal Year 2012: ¥6,760,000 (Direct Cost: ¥5,200,000、Indirect Cost: ¥1,560,000)
• Keywords: 肝炎ウイルス / ウイルス肝炎 / 医療 / 感染症 / C型肝炎

Outline of Final Research Achievements

We have conducted a high throughput screening of chemical library for antiviral compounds against hepatitis C and hepatitis B viruses and acquired the following results. 1. GPx8, a host protein, was cleaved by HCV-NS3/4A serene protease and enhanced viral replication in the host cells. 2. L-carnitine suppressed HCV viral assembly by targeting formation of cellular lipid vesicles. With the above results, it is possible that we can constitute novel antiviral therapeutics against hepatitis viruses.

Research Products

• [Journal Article] Ledipasvir and sofosbuvir fixed-dose combination with and without ribavirin for 12 weeks in treatment-naive and previously treated Japanese patients with genotype 1 hepatitis C: an open-label, randomised, phase 3 trial. (2015)
  • Author(s): Mizokami M, Yokosuka O, Takehara T, Sakamoto N, Korenaga M, Mochizuki H, Nakane K, Enomoto H, Ikeda F, Yanase M, Toyoda H, Genda T, Umemura T, Yatsuhashi H, Ide T et al.
  • Journal Title: Lancet Infect Dis Volume: 印刷中 Issue: 6 Pages: 645-653
  • DOI: 10.1016/s1473-3099(15)70099-x
  • Peer Reviewed / Open Access
• [Journal Article] The JAK2 inhibitor AZD1480 inhibits hepatitis A virus replication in Huh7 cells. (2015)
  • Author(s): Jiang X, Kanda T, Nakamoto S, Saito K, Nakamura M, Wu S, Haga Y, Sasaki R, Sakamoto N, Shirasawa H, Okamoto H, Yokosuka O
  • Journal Title: Biochem Biophys Res Commun Volume: 印刷中 Issue: 4 Pages: 908-912
  • DOI: 10.1016/j.bbrc.2015.02.058
  • Peer Reviewed / Open Access
• [Journal Article] Impaired induction of IL28B and expression of IFNλ4 associated with non-response to interferon-based therapy in chronic hepatitis C. (2015)
  • Author(s): Murakawa M, Asahina Y, Nakagawa M, Sakamoto N, Nitta S, Kusano-Kitazume A, Watanabe T, Kawai-Kitahata F, Otani S, Taniguchi M, Goto F, Nishimura-Sakurai Y, Itsui Y, Azuma S, Kakinuma S, Watanabe M
  • Journal Title: J Gastroenterol Hepatol Volume: 印刷中 Issue: 6 Pages: 1075-84
  • DOI: 10.1111/jgh.12902
  • Peer Reviewed / Open Access
• [Journal Article] Genome-wide association study identifies a PSMD3 variant associated with neutropenia in interferon-based therapy for chronic hepatitis C. (2015)
  • Author(s): Iio E, Matsuura K, Nishida N, Maekawa S, Enomoto N, Nakagawa M, Sakamoto N, Yatsuhashi H et al.
  • Journal Title: Hum Genet Volume: 134 Issue: 3 Pages: 279-289
  • DOI: 10.1007/s00439-014-1520-7
  • Peer Reviewed / Open Access
• [Journal Article] Human Amnion-derived Mesenchymal Stem Cell Transplantation Ameliorates Liver Fibrosis in Rats (2015)
  • Author(s): Onishi R, Ohnishi S, Higashi R, Watari M, Yamahara K, Okubo N, Nakagawa K, Katsurada T, Suda G, Natsuizaka M, Takeda H, Sakamoto N
  • Journal Title: Transplant Direct Volume: 印刷中
  • NAID: 120005773991
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Serum granulysin levels as a predictor of serious telaprevir-induced dermatological reactions. (2015)
  • Author(s): Suda G, Yamamoto Y, Nagasaka A, Furuya K, Kudo M, Chuganji Y, Tsukuda Y, Tsunematsu S, Sato F, Terasita K, Nakai M, Horimoto H, Sho T, Natsuizaka M, Ogawa K, Ohnishi S, Chuma M, Fujita Y, Abe R, Taniguchi M, Nakagawa M, Asahina Y, Sakamoto N
  • Journal Title: Hepatol Res Volume: 印刷中 Issue: 8 Pages: 837-45
  • DOI: 10.1111/hepr.12421
  • NAID: 120005820706
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Once-daily simeprevir in combination with pegylated-interferon and ribavirin: a new horizon in the era of direct-acting antiviral agent therapy for chronic hepatitis C. (2014)
  • Author(s): Maekawa S, Enomoto N
  • Journal Title: J Gastroenterol. Volume: 49(1) Issue: 12 Pages: 163-164
  • DOI: 10.1371/journal.pone.0082299
  • Peer Reviewed
• [Journal Article] Hypoxia-inducible Factors Activate CD133 Promoter through ETS Family Transcription Factors (2013)
  • Author(s): Ohnishi S, Maehara O, Nakagawa K, Kameya A, Otaki K, Fujita H, Higashi R, Takagi K, Asaka M, Sakamoto N, Kobayashi M, Takeda H
  • Journal Title: Plos One Volume: 8 Issue: 6 Pages: e66255-e66255
  • DOI: 10.1371/journal.pone.0066255
  • NAID: 120005326763
  • Peer Reviewed
• [Journal Article] Hepatitis C virus replication is modulated by the interaction of non-structural protein NS5B and fatty acid synthase. (2013)
  • Author(s): Huang JT, Tseng CP, Liao MH, Lu SC, Sakamoto N, et al.
  • Journal Title: Journal of Virology Volume: (Epub) Issue: 9 Pages: 4994-5004
  • DOI: 10.1128/jvi.02526-12
  • Peer Reviewed
• [Journal Article] Hepatitis C virus NS4B protein targets STING and abrogates RIG-I-mediated type-I interferon-dependent innate immunity (2013)
  • Author(s): Nitta S, Sakamoto N, Nakagawa M, Kakinuma S, Mishima K, Kusano-kitazume A, Kiyohashi K, Murakawa M, Nishimura-Sakurai Y, Azuma S, Tasaka-Fujita M, asahina Y, Yoneyama M, Fujita T, Watanabe M
  • Journal Title: Hepatology Volume: 57 Issue: 1 Pages: 46-58
  • DOI: 10.1002/hep.26017
  • Peer Reviewed
• [Journal Article] A multi-center survey of re-treatment with pegylated interferon plus ribavirin combination therapy for patients with chronic Hepatitis C in Japan (2013)
  • Author(s): Oze T, Hiramatsu N, Mita E, Akuta N, Sakamoto N, et al.
  • Journal Title: Hepatol Res Volume: 43 Issue: 1 Pages: 35-43
  • DOI: 10.1111/j.1872-034x.2012.01056.x
  • Peer Reviewed
• [Journal Article] Model incorporating the ITPA genotype identifies patients at high risk of anemia and treatment failure with pegylated-interferon plus ribavirin therapy for chronic hepatitis C. (2013)
  • Author(s): Kurosaki M, Sakamoto N, Asahina Y, Izumi N et al
  • Journal Title: J Med Virol Volume: 85 Issue: 3 Pages: 449-458
  • DOI: 10.1002/jmv.23497
  • Peer Reviewed
• [Journal Article] Add-on therapy of pitavastatin and eicosapentaenoic acid improves outcome of peginterferon plus ribavirin treatment for chronic hepatitis C. (2013)
  • Author(s): Kohjima M, Enjoji M, Sakamoto N, et al.
  • Journal Title: J Med Virol Volume: 85 Issue: 2 Pages: 250-260
  • DOI: 10.1002/jmv.23464
  • Peer Reviewed
• [Journal Article] Inhibition of both protease and helicase activities of hepatitis C virus NS3 by an ethyl acetate extract of marine sponge Haliclona (Reniera) sp. (2013)
  • Author(s): Fujimoto Y, Salam KA, Sakamoto N, et al.
  • Journal Title: Plos One Volume: 7
  • Peer Reviewed
• [Journal Article] Cyclophilin A and nuclear factor of activated T cells are essential in cyclosporin A-mediated suppression of polyomavirus BK replication. (2013)
  • Author(s): Li YJ, Wu HH, Sakamoto N, et al.
  • Journal Title: Am J Transplantation Volume: 12 Pages: 2348-2362
  • Peer Reviewed
• [Journal Article] Factors responsible for the discrepancy between IL28B polymorphism prediction and the viral response to peginterferon plus ribavirin therapy in Japanese chronic hepatitis C patients (2012)
  • Author(s): Saito H, Ito K, Sugiyama M, Matsui T, Aoki Y, Imamura M, Murata K, Masaki N, Nomura H, Adachi H, Hige S, Enomoto N, Sakamoto N, Kurosaki M, Mizokami M, Watanabe S
  • Journal Title: Hepatol Res Volume: 42(10) Issue: 10 Pages: 958-65
  • DOI: 10.1111/j.1872-034x.2012.01013.x
  • Peer Reviewed
• [Journal Article] Inhibition of both protease and helicase activities of hepatitis C virus NS3 by an ethyl acetate extract of marine sponge Amphimedon sp. (2012)
  • Author(s): Fujimoto Y
  • Journal Title: PLoS One. Volume: 7 Issue: 11 Pages: 744-761
  • DOI: 10.1371/journal.pone.0048685
  • Peer Reviewed
• [Journal Article] Anemia and thrombocytosis induced by ribavirin monotherapy in patients with chronic hepatitis C. (2012)
  • Author(s): Kobayashi T, Hige s, Sakamoto N, et al.
  • Journal Title: J Gastroenterol Volume: 47 Issue: 11 Pages: 1228-1237
  • DOI: 10.1007/s00535-012-0579-y
  • NAID: 10031126955
  • Peer Reviewed
• [Journal Article] Ochanomizu Liver Conference Study Group : Association of ITPA gene variant and serum ribavirin concentration with blood cells decline in pegylated interferon-alfa plus ribavirin therapy for chronic hepatitis C. (2012)
  • Author(s): Nakagawa M, Sakamoto N, Watanabe T, et al.
  • Journal Title: Hepatol Int Volume: (Epub)
  • Peer Reviewed
• [Journal Article] Suppression of hepatitis C virus replicon by adenovirus vector-mediated expression of tough decoy RNA against miR-122a. Virus Research (2012)
  • Author(s): Sakurai F, Furukawa N, Higuchi M, Okamoto S, Ono K, Yoshida T, Kondoh M, Yagi K, Sakamoto N, Katayama K, Mizuguchi H
  • Journal Title: EPub ahead of Print Volume: 165 Issue: 2 Pages: 214-218
  • DOI: 10.1016/j.virusres.2012.02.003
  • Peer Reviewed
• [Journal Article] Let-7b is a novel regulator of hepatitis C virus replication. Cell Mol Life Sci 2012 (2012)
  • Author(s): Cheng J-C, Yeh YJ, Tseng CP, Hsu SD, Chang YL, Sakamoto N, Huang HD
  • Journal Title: EPub ahead of Print Volume: 69 Issue: 15 Pages: 2621-2633
  • DOI: 10.1007/s00018-012-0940-6
  • Peer Reviewed
• [Journal Article] Data mining model using simple and readily available factors could identify patients at high risk for hepatocellular carcinoma in chronic hepatitis C (2012)
  • Author(s): Kurosaki M, Sakamoto N, Nakagawa M, et al.
  • Journal Title: J Hepatol Volume: 56(3) Issue: 3 Pages: 602-608
  • DOI: 10.1016/j.jhep.2011.09.011
  • Peer Reviewed
• [Journal Article] Inhibition of hepatitis C virus NS5B polymerase by S-trityl-L-cysteine derivatives (2012)
  • Author(s): Kaushik-Basu N, Sakamoto N
  • Journal Title: Eur J Med Chem Volume: 49 Pages: 191-199
  • DOI: 10.1016/j.ejmech.2012.01.010
  • Peer Reviewed
• [Journal Article] Identification of novel N-(morpholine-4-carbonyloxy) amidine compounds as potent inhibitors against hepatitis C virus replication (2012)
  • Author(s): Kusano-Kitazume A, Sakamoto N, Okuno Y, Sekine-Osajima Y, Nakagawa M, Kakinuma S, Kiyonashi K, Nitta S, Murakawa M, Azuma S, Nishimura-Sakurai Y, Hagiwara M, Watanabe M
  • Journal Title: Antimicrob Agent Chemother Volume: 56(3) Issue: 3 Pages: 1315-23
  • DOI: 10.1128/aac.05764-11
  • Peer Reviewed / Open Access
• [Journal Article] Age and total ribavirin dose are independent predictors of relapse after interferon therapy in chronic hepatitis C revealed by data mining analysis (2012)
  • Author(s): Masayuki Kurosaki
  • Journal Title: Antiviral Therapy Volume: 17(1) Issue: 1 Pages: 35-43
  • DOI: 10.3851/imp1923
  • Peer Reviewed
• [Journal Article] Association of gene expression involving innate immunity and genetic variation in IL28B with antiviral response (2011)
  • Author(s): Asahina Y, Sakamoto N, et al
  • Journal Title: Hepatology Volume: 55(1) Issue: 1 Pages: 20-29
  • DOI: 10.1002/hep.24623
  • Peer Reviewed
• [Presentation] Let-7b is a novel regulator of hepatitis C virus replication. (2012)
  • Author(s): Yeh YJ, Tseng CP, Sakamoto, N, et al.
  • Organizer: 19th. International Meeting on Hepatitis C Virus & Related Viruses
  • Place of Presentation: Palazzio del Chinema (Venice, Italy)
  • Year and Date: 2012-10-05
• [Presentation] 肝線維形成過程におけるMatrix Metalloproteinase-2の機能的意義(シンポジウム8) (2012)
  • Author(s): 柿沼晴、坂本直哉、渡辺守
  • Organizer: 第98回日本消化器病学会総会
  • Place of Presentation: 京王プラザホテル(東京)
  • Year and Date: 2012-04-19
• [Presentation] 宿主遺伝子情報に基づいたC型慢性肝炎治療の効果・安全性の最適化(シンポジウム6) (2012)
  • Author(s): 中川美奈、坂本直哉、渡辺守
  • Organizer: 第98回日本消化器病学会総会
  • Place of Presentation: 京王プラザホテル(東京)
  • Year and Date: 2012-04-19
• [Presentation] IL-6を介したC型慢性肝炎のインターフェロン治療抵抗性機構(シンポジウム3) (2012)
  • Author(s): 坂本直哉、中川美奈、渡辺守
  • Organizer: 第98回日本消化器病学会総会
  • Place of Presentation: 京王プラザホテル(東京)
  • Year and Date: 2012-04-19