新規クラス抗HCV薬開発に向けた抗ウイルス化合物・宿主蛋白の包括的探索

2008 Fiscal Year Annual Research Report

• Project/Area Number: 19390196
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: 坂本 直哉 Tokyo Medical and Dental University, 大学院・医歯学総合研究科, 寄附講座准教授 (10334418)
• Co-Investigator(Kenkyū-buntansha): 田坂 めぐみ 東京医科歯科大学, 医学部・附属病院, 医員 (50510369)
• Keywords: HCVレプリコン / HVC-JFH1培養系

Research Abstract

当該研究期間において我々は、HCV感染・増殖細胞モデルを用いて薬剤・生理活性化合物・短鎖ペプチドの抗ウイルス作用の網羅的スクリーニング、およびHCV増殖に関連する宿主因子の探索を遂行し、以下の結果を得た。(1)HCV-Feo replicon細胞を用いてDiversity-Oriented Synthesis (DOS)法で合成した8,000種の化合物のスクリーニングを施行し、HCV増殖を抑制する41種の化合物を同定し、構造活性相関解析にIC50の優れた5個のepoxide誘導体を同定した。(2)HCV複製増殖に関与する代謝・シグナルネットワークの網羅的解析により、脂質・コレステロール代謝に関わる代謝・シグナルネットワークの関与、関連薬剤の効果を確認した。(3)漢方生薬成分化合物の細胞内HCV増殖に対する効果をHCVレプリコンシステムを用いて解析を行い、甘草由来の2種の化合物、isoliquiritigenin、及びglycycoumarinにHCV増殖抑制作用を見出した。今後これらの知見を統合し、HCV感染サイクルにおけるウイルスおよび宿主蛋白相互作用の細胞・分子レベルでの理解を深め、新規クラス抗HCV療法薬剤の開発・実用化に必要な基盤情報の蓄積を到達目標とし引き続き研究を遂行する。本研究で同定された化合物の作用機構の解析、小動物モデルを用いた効果・安全性の検証を進めることにより新たな抗ウイルス薬剤の開発につながると思われる。

Research Products

• [Journal Article] A functional genomic screen identifies cellular cofactors of hepatitis C virus replication. (2009)
  • Author(s): Andrew W. Tai, Yair Benita, Lee F. Peng, Sun-Suk Kim, Naoya Sakamoto, Ramnik J. Xavier, Raymond T. Chung
  • Journal Title: Cell Host & Microbe In press
  • Peer Reviewed
• [Journal Article] Signaling pathway via TNFa/NFnB in intestinal epithelial cells may be directly involved in colitis-associated carcinogenesis. (2009)
  • Author(s): Onizawa, Kanai T, Totsuka T, Okamoto R, Tsuchiya K, Nemoto Y, Nagaishi T, Sakamoto N, Watanabe M
  • Journal Title: Am J Physiol Gastrointest Liver Physiol In press
  • Peer Reviewed
• [Journal Article] Synergistic inhibition of intracellular hepatitis C virus replication by nelfinavir and interferon-a. (2009)
  • Author(s): Satoshi Toma, Tsuyoshi Yamashiro, Shingo Arakaki, Joji Shiroma, Tatsuji Maeshiro, Kenji Hibiya, Naoya Sakamoto, Fukunori Kinjo, Masao Tateyama, Jiro Fujita
  • Journal Title: Journal of Viral Hepatitis In press
  • Peer Reviewed
• [Journal Article] Two flavonoids extracts from a herb, Glycyrrhizae radix, inhibit in-vitro hepatitis C virus replication. (2009)
  • Author(s): Sekine-Osajima Y, Sakamoto N, Nakagawa M, Itsui Y, Tasaka M, Nishimura-Sakurai Y, Chen CH, Suda G, Mishima K, Onuki Y, Yamamoto M, Maekawa S, Enomoto N, Kanai T, Tsuchiya K, Watanabe M
  • Journal Title: Hepatoloj Res 39 Pages: 60-69
  • Peer Reviewed
• [Journal Article] FTY720 suppresses the development of colitis in lymphoid-null mice by modulating the trafficking of colitogenic CD4+ T cells in bone marrow. (2008)
  • Author(s): Fujii T, Kanai T, Tomita T, Nemoto Y, Totsuka T, Sakamoto N, Nakamura T, Tsuchiya K, Okamoto R, Watanabe M
  • Journal Title: Eur J Immunol 38 Pages: 3290-3303
  • Peer Reviewed
• [Journal Article] Inhibition of hepatitis C virus infection and expression in vitro and in vivo by recombinant adenovirus expressing short hairpin RNA. (2008)
  • Author(s): Sakamoto N, Tanabe Y, Yokota T, Saito K, Sekine-Osajima Y, Nakagawa M, Itsui Y, Tasaka M, Sakurai Y, Chen CH, Yano M, Ohkoshi S, Aoyagi Y, Maekawa S, Enomoto N, Kohara M, Watanabe M
  • Journal Title: J Gastro Hepatol 23 Pages: 1437-1447
  • Peer Reviewed
• [Journal Article] Effects of immunosuppressants on the progression of hepatitis C in hepatitis C virus-positive renal transplantation and the usefulness of interferon therapy. (2008)
  • Author(s): Nanmoku K, Imaizumi R, Tojimbara T, Nakajima I, Fuchinoue S, Sakamoto N, Watanabe M, Teraoka S
  • Journal Title: Transplant Proc 40 Pages: 2382-2385
  • Peer Reviewed
• [Journal Article] Griseofulvin, an oral antifungal agent, suppresses HCV replication in vitro. (2008)
  • Author(s): Jin H, Yamashita A, Maekawa S, Yang P, He L, Takayanagi S, Wakita T, Sakamoto N, Enomoto N, Ito M
  • Journal Title: Hepatology Res 38 Pages: 909-918
  • Peer Reviewed
• [Journal Article] Continuous generation of colitogenic CD4+ T cells may be one of the mechanisms to persist colitis. (2008)
  • Author(s): Tomita T, Kanai T, Fujii T, Nemoto Y, Okamoto R, Tsuchiya K, Totsuka T, Sakamoto N. Watanabe M
  • Journal Title: Eur J Immunol 38 Pages: 1264-1274
  • Peer Reviewed
• [Journal Article] MyD88-dependent Pathway in T Cells Directly Modulates the Expansion of Colitogenic CD4+ T Cells in Chronic Colitis. (2008)
  • Author(s): Tomita T, Kanai T, Fujii T, Nemoto Y, Okamoto R, Tsuchiya K, Totsuka T, Sakamoto N. Akira S, Watanabe M
  • Journal Title: J Immunol 180 Pages: 5291-5299
  • Peer Reviewed
• [Journal Article] Potential relevance of cytoplasmic viral sensors and related regulators involving innate immunity in antiviral response. (2008)
  • Author(s): Asahina Y, Izumi N, Hirayama I, Tanaka T, Sato M, Yasui Y, Komatsu N, Umeda N, Hosokawa T, Ueda K, Tsuchiya K, Nakanishi H, Itakura J, Kurosaki M, Enomoto N, Tasaka M, Sakamoto N, Miyake S
  • Journal Title: Gastroenterology 134 Pages: 1396-1405
  • Peer Reviewed
• [Journal Article] Immunosenescent colitogenic CD4+ T cells convert to regulatory cells and suppress colitis. (2008)
  • Author(s): Totsuka T, Kanai T, Nemoto Y, Tomita T, Tsuchiya K, Sakamoto N, Okamoto R, Watanabe M
  • Journal Title: Eur J Immunol 38 Pages: 1275-1286
  • Peer Reviewed
• [Journal Article] Proteasomal degradation of Atohl by aberrant Wnt signaling maintains the undifferentiated state of colon cancer. (2008)
  • Author(s): Aragaki M, Tsuchiya K, Okamoto R, Yoshioka S, Nakamura T, Sakamoto N, Kanai T, Watanabe M
  • Journal Title: Biochem Biophys Res Commun 368 Pages: 923-929
  • Peer Reviewed
• [Journal Article] Targeting lipid metabolism in the treatment of hepatitis C. (2008)
  • Author(s): Amemiya F, Maekawa S, Itakura Y, Kanayama A, Takano S, Yamaguchi T, Itakura J, Kitamura T, Inoue T, Sakamoto M, Yamauchi K, Okada S, Sakamoto N, Enomoto N
  • Journal Title: J Infect Dis 368 Pages: 361-370
  • Peer Reviewed
• [Journal Article] Development of plaque assays for hepatitis C virus and isolation of mutants with enhanced cytopathogenicity and replication capacity. (2008)
  • Author(s): Sekine-Osajima Y, Sakamoto N (equal contribution), Nakagawa M, Itsui Y, Tasaka M, Nishimura-Sakurai Y, Chen CH, Kanai T, Tsuchiya K, Wakita T, Enomoto N, Watanabe M
  • Journal Title: Virology 368 Pages: 71-85
  • Peer Reviewed
• [Presentation] Establishment and genetic analyzes of cytopathogenic HCV-JFH1 mutants by plaque-forming assay. (2008)
  • Author(s): Kako Mishima, Naoya Sakamoto. Yuko Sekine-Osajima, Mina Nakagawa, Megumi Tasaka, Yuki Nishimura-Sakurai, Yasuhiro Itsui, Takaji Wakita, Mamoru Watanabe
  • Organizer: Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: San Francisco, CA, USA
  • Year and Date: 2008-11-01
• [Presentation] Suppression of interferon induction and response pathway by Hepatitis C virus NS4B. (2008)
  • Author(s): M. Tasakal, N. Sakamoto, M. Nakagawa, Y. Itsui, Y. Nishimura-Sakurai, C. Chen, Goki Suda, Kako Mishima, Machi Yamamoto, Yuko Onuki, M. Watanabe
  • Organizer: Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: San Francisco, CA, USA
  • Year and Date: 2008-11-01
• [Presentation] Pretreatment assessment of PEG-interferon plus ribavirin anti-HCV therapy using viral genetic profiles, NS5A-ISDR and Core mutations. (2008)
  • Author(s): Naoya Sakamoto, Mina Nakagawa, Cheng-Hsin Chen, Yasuhiro Itsui, Megumi Tasaka, Nobuyuki Enomoto, Mamoru Watanabe
  • Organizer: Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: San Francisco, CA, USA
  • Year and Date: 2008-11-01
• [Presentation] THE ISOMERASE ACTIVITY OF CYCLOPHILIN A IS CRITICAL FOR HCV REPLICATION. (2008)
  • Author(s): Bobardt M., Chatterji U., Selvarajah S., Tang H., Sakamoto N., Coelmont L., Neyts J., Dumont J. -M., Vuagniaux G., Gallay P.
  • Organizer: 15th. International Meeting on Hepatitis C Virus & Related Viruses.
  • Place of Presentation: San Antonio, TX, USA
  • Year and Date: 2008-10-04
• [Presentation] Establishment and genetic analyzes of cytopathogenic HCV-JFHI mutants by plaque-forming assay. (2008)
  • Author(s): Naoya Sakamoto, Kako Mishima, Yuko Sekine-Osajima, Mina Nakagawa, Megumi Tasaka, Yuki Nishimura-Sakurai, Yasuhiro Itsui, Takaji Wakita, Mamoru Watanabe
  • Organizer: 15th. International Meeting on Hepatitis C Virus & Related Viruses.
  • Place of Presentation: San Antonio, TX, USA
  • Year and Date: 2008-10-04
• [Presentation] A novel NS5B-interacting protein modulates hepatitis C virus replication. (2008)
  • Author(s): Jing-Tang Huang, Ching-Ping Tseng, Naoya Sakamoto, Shao-Chun Lu, Chuan-Mu Chen, Ju-Chien Cheng
  • Organizer: 15th. International Meeting on Hepatitis C Virus & Related Viruses.
  • Place of Presentation: San Antonio, TX, USA
  • Year and Date: 2008-10-04