ウイルス感染増殖系を基盤とした天然化合物新規生理機能の同定
Publicly Offered Research
Project Area | Chemical Biology using bioactive natural products as specific ligands: identification of molecular targets and regulation of bioactivity |
Project/Area Number |
26102747
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Research Category |
Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
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Allocation Type | Single-year Grants |
Review Section |
Science and Engineering
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Research Institution | National Institute of Infectious Diseases |
Principal Investigator |
渡士 幸一 国立感染症研究所, ウイルス第二部, 主任研究官 (40378948)
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Project Period (FY) |
2014-04-01 – 2016-03-31
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Project Status |
Completed (Fiscal Year 2015)
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Budget Amount *help |
¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
Fiscal Year 2015: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Fiscal Year 2014: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
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Keywords | 天然物 / ウイルス / 肝炎ウイルス / 複製 / 侵入 / HCV / LXR / 転写 |
Outline of Annual Research Achievements |
真菌二次代謝産物由来天然化合物ライブラリーより、neoechinulin B (NeoB)がC型肝炎ウイルス(HCV)複製を抑制することを見出した。NeoBは細胞毒性をほとんど示すことなく用量依存的にHCV複製及びそれによる粒子作成を抑制した。またトランスクリプトーム解析及びレポーターアッセイより、NeoBは肝細胞内のliver X receptor (LXR)の転写活性を特異的に阻害することが明らかとなった。また誘導体解析より、この活性にはNeoB内のジケトピペラジン骨格が重要であることも示唆された。NeoBはLXRに直接相互作用することでその転写活性を阻害し、LXR下流遺伝子の発現調節を脱制御することで、肝細胞内脂質代謝等を修飾すると考えられた。neoechinulin BによりLXR活性を低下させたHCV感染細胞においては、HCV複製の場と考えられている二重膜ベシクル形成が大きく低下していることが観察された。以上のことより、本研究ではNeoBが新規LXRアンタゴニストであることが示唆された。またNeoBによるLXR不活性化はウイルス複製の場形成低下を介してHCV産生を減少させると考えられた。 一方本研究では同じライブラリーより、B型肝炎ウイルス(HBV)感染を低下させる新規三環系ポリケチドを同定し、これをvanitaracin Aと命名した。vanitaracin Aは細胞毒性を示すことなく用量依存的にHBV侵入を低下させ、その活性はIC50 = 0.61 uM, CC50 > 256 uMであった。生化学的アッセイ及び表面プラズモン共鳴により、vanitaracin AはHBV受容体であるNTCPに直接相互作用するリガンドであることを明らかにした。vanitaracin Aは様々な遺伝子型のHBV感染を阻害し、また同じくNTCP依存的に感染するD型肝炎ウイルス感染も阻害する一方で、NTCP非依存的なHCV感染にはほとんど影響を与えなかった。このようにvanitaracin Aは新たな抗HBV剤の有用なリード化合物になると期待される。
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Research Progress Status |
27年度が最終年度であるため、記入しない。
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Strategy for Future Research Activity |
27年度が最終年度であるため、記入しない。
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Report
(2 results)
Research Products
(123 results)
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[Journal Article] Prolactin Regulatory Element Binding Protein Is Involved in Hepatitis C Virus Replication by Interaction with NS4B2016
Author(s)
Kong L, Fujimoto A, Nakamura M, Aoyagi H, Matsuda M, Watashi K, Suzuki R, Arita M, Yamagoe S, Dohmae N, Suzuki T, Sakamaki Y, Ichinose S, Suzuki T, Wakita T, Aizaki H
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Journal Title
J Virol
Volume: 90
Issue: 6
Pages: 3093-3111
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Anti-hepatitis C Virus Natural Product from a Fungus, Penicillium herquei2016
Author(s)
Nishikori S, Takemoto K, Kamisuki S, Nakajima S, Kuramochi K, Tsukuda S, Iwamoto M, Katayama Y, Suzuki T, Kobayashi S, Watashi K, Sugawara F
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Journal Title
J Nat Prod
Volume: 79
Issue: 2
Pages: 442-446
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
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[Journal Article] Single-domain Intrabodies against HCV Core Inhibit Viral Propagation and Core-induced NF-κB Activation2016
Author(s)
Suzuki R, Saito K, Matsuda M, Sato M, Kanegae Y, Shi G, Watashi K, Aizaki H, Chiba J, Saito I, Wakita T, Suzuki T
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Journal Title
J Gen Virol
Volume: 印刷中
Issue: 4
Pages: 887-892
DOI
Related Report
Peer Reviewed / Acknowledgement Compliant
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[Journal Article] Hepatocyte Factor JMJD5 Regulates Hepatitis B Virus Replication through Interaction with HBx2016
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
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Journal Title
J Virol
Volume: 90
Issue: 7
Pages: 3530-3542
DOI
Related Report
Peer Reviewed
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[Journal Article] Inhibition of preS1-hepatocyte interaction by an array of recombinant human antibodies from naturally recovered individuals2016
Author(s)
Sankhyan A, Sharma C, Dutta D, Sharma T, Chosdol K, Wakita T, Watashi K, Awasthi A, Acharya SK, Khanna N, Tiwari A, Sinha S
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Journal Title
Sci Rep
Volume: 6
Issue: 1
Pages: 21240-21240
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Novel Robust in Vitro Hepatitis B Virus Infection Model Using Fresh Human Hepatocytes Isolated from Humanized Mice.2015
Author(s)
Ishida Y, Yamasaki C, Yanagi A, Yoshizane Y, Fujikawa K, Watashi K, Abe H, Wakita T, Hayes CN, Chayama K, Tateno C.
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Journal Title
Am J Pathol.
Volume: 185
Issue: 5
Pages: 1275-1285
DOI
Related Report
Peer Reviewed
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[Journal Article] Amino acid polymorphisms in hepatitis C virus core affect infectious virus production and major histocompatibility complex class I molecule expression2015
Author(s)
Tasaka-Fujita M, Sugiyama N, Kang W, Masaki T, Murayama A, Yamada N, Sugiyama R, Tsukuda S, Watashi K, Asahina Y, Sakamoto N, Wakita T, Shin EC, Kato T
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Journal Title
Sci Rep
Volume: 5
Issue: 1
Pages: 13994-14002
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
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[Journal Article] A Novel Tricyclic Polyketide, Vanitaracin A, Specifically Inhibits the Entry of Hepatitis B and D Viruses by Targeting Sodium Taurocholate Cotransporting Polypeptide2015
Author(s)
Kaneko M, Watashi K, Kamisuki S, Matsunaga H, Iwamoto M, Kawai F, Ohashi H, Tsukuda S, Shimura S, Suzuki R, Aizaki H, Sugiyama M, Park SY, Ito T, Ohtani N, Sugawara F, Tanaka Y, Mizokami M, Sureau C, Wakita T
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Journal Title
J Virol
Volume: 89
Issue: 23
Pages: 11945-11953
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
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[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
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Journal Title
Marine Drug
Volume: 13
Issue: 11
Pages: 6759-6773
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
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[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.
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Journal Title
Scientific reports
Volume: 5
Issue: 1
Pages: 17047-17047
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Disparity of basal and therapeutically activated interferon signalling in constraining hepatitis E virus infection2015
Author(s)
Zhou X, Xu L, Wang W, Watashi K, Wang Y, Sprengers D, de Ruiter PE, van der Laan LJ, Metselaar HJ, Kamar N, Peppelenbosch MP, Pan Q
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Journal Title
J Viral Hepat
Volume: 23
Issue: 4
Pages: 294-304
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] The RNA Sensor RIG-I Dually Functions as an Innate Sensor and Direct Antiviral Factor for Hepatitis B Virus2015
Author(s)
Sato S, Li K, Kameyama T, Hayashi T, Ishida Y, Murakami S, Watanabe T, Iijima S, Sakurai Y, Watashi K, Tsutsumi S, Sato Y, Akita H, Wakita T, Rice CM, Harashima H, Kohara M, Tanaka Y, Takaoka A
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Journal Title
Immunity
Volume: 42
Issue: 1
Pages: 123-132
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Dysregulation of retinoic acid receptor diminishes hepatocyte permissiveness to hepatitis B virus infection through modulation of sodium taurocholate cotransporting polypeptide (NTCP) expression.2015
Author(s)
Tsukuda S, Watashi K, Iwamoto M, Suzuki R, Aizaki H, Okada M, Sugiyama M, Kojima S, Tanaka Y, Mizokami M, Li J, Tong S, Wakita T.
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Journal Title
J Biol Chem.
Volume: 290
Issue: 9
Pages: 5673-84
DOI
Related Report
Peer Reviewed / Open Access
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[Presentation] 海綿由来セキステルペン系化合物metachromin AのB型肝炎ウイルスコアプロモーター抑制活性を介した抗ウイルス活性2015
Author(s)
山下篤哉, 田中智久, 土橋香織, 葛西宏威, 渡士幸一, 脇田隆字, 外山正明, 馬場昌範, 前川伸哉, 榎本信幸, 玉城麻友美, 田中淳一, 森石恆司
Organizer
BMB 2015
Place of Presentation
神戸
Year and Date
2015-12-02
Related Report
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[Presentation] Development of a novel vaccine platform based on Japanese encephalitis viruses2015
Author(s)
Suzuki R, Saga R, Fujimoto A, Watanabe N, Matsuda M, Hasegawa M, Watashi K, Aizaki H, Nakamura N, Konishi E, Kato T, Tajima S, Takasaki T, Takeyama H, Wakita T
Organizer
BMB 2015
Place of Presentation
神戸
Year and Date
2015-12-02
Related Report
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[Presentation] Transfer hepatitis C virus from human liver cells to hepatic stellate cells2015
Author(s)
Zaitsu T, Aoyagi H, Fujimoto A, Matsuda M, Watanabe N, Watashi K, Suzuki R, Fukuhara T, Matsuura Y, Sakamaki Y, Ichinose S, Wake K, Suzuki T, Iijima H, Matsuura T, Tamura K, Wakita T, Aizaki H
Organizer
第63回日本ウイルス学会学術集会
Place of Presentation
福岡
Year and Date
2015-11-23
Related Report
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[Presentation] Identification of flavonoid derivative that directly acts on hepatitis B virus surface protein and inhibits viral entry2015
Author(s)
Tsukuda S, Watashi K, Hamada Y, Isogawa M, Iwamoto M, Suzuki R, Aizaki H, Kojima S, Sugiyama M, Saito A, Tanaka Y, Mizokami M, Wakita T
Organizer
第63回日本ウイルス学会学術集会
Place of Presentation
福岡
Year and Date
2015-11-23
Related Report
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[Presentation] Investigation of mechanisms of interaction between host glycosylation system and hepatitis B virus replication system2015
Author(s)
Okutsu S, Ito K, Yoneda M, Angata K, Watashi K, Wakita T, Iijima S, Tanaka Y, Tong S, Mizokami M, Narimatsu H
Organizer
第63回日本ウイルス学会学術集会
Place of Presentation
福岡
Year and Date
2015-11-23
Related Report
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[Presentation] Bivalent vaccine platform based on Japanese encephalitis virus (JEV) elicit neutralizing antibodies against JEV and hepatitis C virus2015
Author(s)
Saga R, Fujimoto A, Watanabe N, Matsuda M, Hasegawa M, Watashi K, Aizaki H, Nakamura N, Konishi E, Kato T, Tajima S, Takasaki T, Takeyama H, Wakita T, Suzuki R
Organizer
第63回日本ウイルス学会学術集会
Place of Presentation
福岡
Year and Date
2015-11-23
Related Report
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[Presentation] A new fungi-derived vanitaracin A specifically inhibits the entry of hepatitis B and D viruses through interacting with NTCP2015
Author(s)
Kaneko M, Watashi K, Kamisuki S, Matsunaga H, Iwamoto M, Kawai F, Ohashi H, Tsukuda S, Shimura S, Suzuki R, Aizaki H, Sugiyama M, Park Sy, Ohtani N, Sugawara F, Tanaka Y, Mizokami M, Wakita T
Organizer
第63回日本ウイルス学会学術集会
Place of Presentation
福岡
Year and Date
2015-11-23
Related Report
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[Presentation] Surfeit 4 is involved in HCV replication by interacting with NS4B2015
Author(s)
Kong L, Aoyagi H, Matsuda M, Fujimoto A, Watashi K, Suzuki R, Yamagoe S, Dohmae N, Suzuki T, Sakamaki Y, Ichinose S, Suzuki T, Wakita T, Aizaki H
Organizer
第63回日本ウイルス学会学術集会
Place of Presentation
福岡
Year and Date
2015-11-23
Related Report
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[Presentation] Flutamide-mediated disruption of lipid droplets impairs the host permisiveness to hepatitis C virus production2015
Author(s)
Ohashi H, Watashi K, Nakajima S, Kim S, Suzuki R, Aizaki H, Fukasawa M, Kamisuki S, Sugawara F, Ohtani N, Wakita T
Organizer
第63回日本ウイルス学会学術集会
Place of Presentation
福岡
Year and Date
2015-11-23
Related Report
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[Presentation] Metachromin A, sesquiterpene from marine sponge Dactylospongia metachromia, exerts anti-HBV activity via inhibition of HBV core promoter2015
Author(s)
Yamashita A, Tanaka T, Okuyama-Dobashi K, Kasai H, Watashi K, Wakita T, Toyama M, Baba M, Moriishi K
Organizer
第63回日本ウイルス学会学術集会
Place of Presentation
福岡
Year and Date
2015-11-23
Related Report
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[Presentation] Japanese encephalitis virus (JEV)-subviral particles harboring HCV neutralization epitopes elicit neutralizing antibodies against JEV and HCV2015
Author(s)
Saga R, Fujimoto A, Watanabe N, Matsuda M, Hasegawa M, Watashi K, Aizaki H, Nakamura N, Konishi E, Kato T, Takeyama H, Wakita T, Suzuki R
Organizer
22nd International Symposium on Hepatitis C Virus and Related Viruses
Place of Presentation
Strasbourg (France)
Year and Date
2015-10-11
Related Report
Int'l Joint Research
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[Presentation] Identification of HBV entry inhibitors, based on the cyclosporin structure2015
Author(s)
Shimura S, Watashi K, Sluder A, Peel M, Kawai F, Sugiyama M, Park SY, Tanaka Y, Mizokami M, Wakita T
Organizer
2015 International Meeting of Molecular Biology of Hepatitis B Viruses
Place of Presentation
Bad Nauheim(Germany)
Year and Date
2015-10-07
Related Report
Int'l Joint Research
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[Presentation] Dual function of RIG-I as innate antiviral mediator against hepatitis B virus2015
Author(s)
Sato S, Li K, Kameyama T, Hayashi T, Ishida Y, Murakami S, Watanabe T, Iijima S, Sakurai Y, Watashi K, Tsutsumi S, Sato Y, Akita H, Wakita T, Rice Cm, Harashima H, Kohara M, Tanaka Y, Takaoka A
Organizer
2015 International Meeting of Molecular Biology of Hepatitis B Viruses
Place of Presentation
Bad Nauheim(Germany)
Year and Date
2015-10-07
Related Report
Int'l Joint Research
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[Presentation] Identification of a new tricyclic polyketide, vanitaracin A, which inhibits the entry of HBV, HDV, and nucleoside analog-resistant HBV though targeting NTCP2015
Author(s)
Kaneko M, Watashi K, Kamisuki S, Matsunaga H, Iwamoto M, Kawai F, Ohashi H, Tsukuda S, Shimura S, Suzuki R, Aizaki H, Sugiyama M, Park SY, Ohtani N, Sugawara F, Tanaka Y, Mizokami M, Sureau C, Wakita T
Organizer
2015 International Meeting of Molecular Biology of Hepatitis B Viruses
Place of Presentation
Bad Nauheim(Germany)
Year and Date
2015-10-07
Related Report
Int'l Joint Research
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[Presentation] Identification of NTCP-targeting small molecules that inhibit HBV entry by cell-based and in vitro technologies2015
Author(s)
Watashi K, Tsukuda S, Shimura S, Kaneko M, Sluder A, Peel M, Kamisuki S, Matsunaga S, Morishita R, Futamura Y, Kondoh Y, Suzuki R, Aizaki H, Sugiyama M, Borroto-Esoda K, Ryo A, Sugawara F, Osada H, Tanaka Y, Mizokami M, Wakita T
Organizer
2015 International Meeting of Molecular Biology of Hepatitis B Viruses
Place of Presentation
Bad Nauheim(Germany)
Year and Date
2015-10-07
Related Report
Int'l Joint Research
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[Presentation] Investigation of the mechanism of interaction between host glycosylation system and hepatitis B virus replication system2015
Author(s)
Ito K, Yoneda M, Angata K, Watashi K, Wakita T, Iijima S, Tanaka Y, Tong S, Kuno A, Sugiyama M, Mizokami M, Narimatsu H
Organizer
2015 International Meeting of Molecular Biology of Hepatitis B Viruses
Place of Presentation
Bad Nauheim(Germany)
Year and Date
2015-10-07
Related Report
Int'l Joint Research
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[Presentation] 新規真菌二次代謝産物 SF177 の B 型肝炎ウイルス感染阻害活性および NTCP トランスポーター阻害活性の同定2015
Author(s)
金子学, 渡士幸一, 松永大輝, 紙透伸治, 岩本将士, 河合文啓, 鈴木亮介, 相崎英樹, 朴三用, 菅原二三男, 脇田隆字
Organizer
第25回抗ウイルス療法学会総会
Place of Presentation
東京
Year and Date
2015-05-23
Related Report
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[Presentation] B型肝炎ウイルスに対する直接標的薬proanthocyanidinおよび宿主標的薬vanitaracinの同定および感染阻害機構の解析2015
Author(s)
渡士幸一, 九十田千子, 金子学, 松永大輝, 紙透伸治, 齊藤安貴子, 鈴木亮介, 相崎英樹, 杉山真也, 溝上雅史, 菅原二三男, 田中靖人, 脇田隆字
Organizer
第25回抗ウイルス療法学会総会
Place of Presentation
東京
Year and Date
2015-05-23
Related Report
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[Presentation] Neoechinulin Bのliver X receptor転写阻害効果の同定およびそれによるC型肝炎ウイルス複製制御機構の解析2015
Author(s)
渡士幸一, 中嶋翔, 紙透伸治, Izaguirre-Carbonell J, Kwon Atj, 鈴木治和, 九十田千子, 岡田麻衣子, 鈴木亮介, 相崎英樹, 菅原二三男, 脇田隆字
Organizer
第25回抗ウイルス療法学会総会
Place of Presentation
東京
Year and Date
2015-05-23
Related Report
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[Presentation] カイメン由来化合物metachromin A及びその類縁化合物の抗HBV活性の検討2015
Author(s)
山下篤哉, 田中智久, 葛西宏威, 渡士幸一, 脇田隆字, 外山政明, 馬場昌範, 前川伸哉, 榎本信幸, 玉城麻友美, 田中淳一, 森石恆司
Organizer
第25回抗ウイルス療法学会総会
Place of Presentation
東京
Year and Date
2015-05-23
Related Report
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[Presentation] B型肝炎ウイルスの感染に対するRIG-Iを介した自然免疫応答機構2015
Author(s)
佐藤精一, 李凱, 亀山武志, 林隆也, 石田雄二, 村上周子, 渡邊綱正, 飯島沙幸, 櫻井遊, 渡士幸一, 堤進, 佐藤悠介, 秋田英万, 脇田隆字, Rice Cm, 原島秀吉, 小原道法, 田中靖人, 高岡晃教
Organizer
第25回抗ウイルス療法学会総会
Place of Presentation
東京
Year and Date
2015-05-23
Related Report
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[Presentation] NTCP as a drug target of anti-hepatitis B virus infection2015
Author(s)
Watashi K
Organizer
2015 American Association of Pharmaceutical Scientists (AAPS)/ International Transporter Consortium (ITC) Workshop on Drug Transporter in ADME: From the Bench to the Bedside
Place of Presentation
Baltimore (USA)
Year and Date
2015-04-21
Related Report
Int'l Joint Research / Invited
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[Presentation] Japanese Encephalitis Virus-subviral particles harboring HCV neutralization epitopes induce neutralizing antibodies against HCV2014
Author(s)
Saga R, Fujimoto A, Watanabe N, Matsuda M, Hasegawa M, Watashi K, Aizaki H, Nakamura N, Konishi E, Kato T, Takeyama H, Wakita T, Suzuki R
Organizer
21th International Symposium on Hepatitis C Virus and Related Viruses
Place of Presentation
Banff (Canada)
Year and Date
2014-09-09
Related Report
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[Presentation] Single domain intrabodies against HCV core inhibit viral propagation and core-induced NF-kB activation2014
Author(s)
Suzuki R, Saito K, Matsuda M, Sato M, Kanegae Y, Watashi K, Aizaki H, Chiba J, Saito I, Wakita T, Suzuki T
Organizer
21th International Symposium on Hepatitis C Virus and Related Viruses
Place of Presentation
Banff (Canada)
Year and Date
2014-09-09
Related Report
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[Presentation] NS5A-associated membrane protein, embryonic lethal, abnormal vision, drosophila-like 1, regulates hepatitis C virus RNA synthesis and translation2014
Author(s)
Goto K, Fujimoto A, Watashi K, Suzuki R, Yamagoe S, Moriya K, Yotsuyanagi H, Koike K, Suzuki T, Miyamura T, Wakita T, Aizaki H
Organizer
21th International Symposium on Hepatitis C Virus and Related Viruses
Place of Presentation
Banff (Canada)
Year and Date
2014-09-09
Related Report
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[Presentation] Characterization of a culture system reproducing the NTCP-mediated HBV entry and its application to drug development2014
Author(s)
Watashi K, Iwamoto M, Sluder A, Matsunaga S, Ryo A, Morishita R, Kwon ATJ, Suzuki H, Tsukuda S, Suzuki R, Aizaki H, Borroto-Esoda K, Sugiyama M, Tanaka Y, Mizokami M, Wakita T
Organizer
2014 International Meeting on the Molecular Biology of Hepatitis B Viruses
Place of Presentation
Los Angeles (USA)
Year and Date
2014-09-03
Related Report
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