Analysis of dengue virus replication mechanism using small molecule compounds

• Project/Area Number: 17K08870
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Virology
• Research Institution: Kanagawa Prefectural Institute of Public Health (2018-2020); Tokyo Metropolitan Institute of Medical Science (2017)
• Principal Investigator: Hishiki Takayuki 神奈川県衛生研究所, 微生物部, 主任研究員 (30535761)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: デングウイルス / ジカウイルス / 抗ウイルス化合物 / ウイルス複製機構 / ケミカルバイオロジー / 複製機構

Outline of Final Research Achievements

Dengue virus (DENV), transmitted to humans by Aedes mosquitoes, is the aetiological agent of dengue fever and dengue haemorrhagic fever and continues to be a public health problem in the tropical and subtropical areas. However, there is currently no antiviral treatment for DENV infection. In this study, our aim was to analyze the DENV replication mechanism and obtain basic information leading to the development of new antiviral agents. As a result of analysis using infectious DENV and replicon cells, we identified some compounds that have potent anti-DENV activity and low cytotoxicity.

Academic Significance and Societal Importance of the Research Achievements

抗ウイルス化合物の同定と分子作用機序の解明は、デングウイルス生活環の新たな側面を明らかにするだけでなく、他のウイルス複製機構の解明、さらには宿主細胞の理解への波及効果をもたらす事が予想される。またそれらの知見は、新たな創薬標的分子を見いだすことに繋がり、より効率的な抗ウイルス剤開発への応用が期待される。さらに今回同定した抗ウイルス化合物のなかには承認薬も含まれている事から、ドラッグリポジショニングによる新薬開発に繋がる可能性がある。

Research Products

• [Journal Article] Sphingomyelin Is Essential for the Structure and Function of the Double-Membrane Vesicles in Hepatitis C Virus RNA Replication Factories (2020)
  • Author(s): Gewaid H, Aoyagi H, Arita M, Watashi K, Suzuki R, Sakai S, Kumagai K, Yamaji T, Fukasawa M, Kato F, Hishiki T, Mimata A, Sakamaki Y, Ichinose S, Hanada K, Muramatsu M, Wakita T, Aizaki H.
  • Journal Title: J Virol Volume: 94 Issue: 23
  • DOI: 10.1128/jvi.01080-20
  • Peer Reviewed
• [Journal Article] Antiviral activities of mycophenolic acid and IMD‐0354 against SARS‐CoV‐2 (2020)
  • Author(s): Kato Fumihiro、Matsuyama Shutoku、Kawase Miyuki、Hishiki Takayuki、Katoh Hiroshi、Takeda Makoto
  • Journal Title: Microbiology and Immunology Volume: 64 Issue: 9 Pages: 635-639
  • DOI: 10.1111/1348-0421.12828
  • Peer Reviewed
• [Journal Article] Identification of inhibitors of dengue viral replication using replicon cells expressing secretory luciferase (2019)
  • Author(s): Kato Fumihiro、Nio Yasunori、Yagasaki Kazumi、Suzuki Rieko、Hijikata Makoto、Miura Tomoyuki、Miyazaki Isao、Tajima Shigeru、Lim Chang-Kweng、Saijo Masayuki、Takasaki Tomohiko、Hishiki Takayuki
  • Journal Title: Antiviral Research Volume: 172 Pages: 104643-104643
  • DOI: 10.1016/j.antiviral.2019.104643
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Synthesis and biological evaluation of novel imidazole nucleosides as potential anti-dengue virus agents (2019)
  • Author(s): Okano Yuki、Saito-Tarashima Noriko、Kurosawa Madoka、Iwabu Ai、Ota Masashi、Watanabe Tadashi、Kato Fumihiro、Hishiki Takayuki、Fujimuro Masahiro、Minakawa Noriaki
  • Journal Title: Bioorganic & Medicinal Chemistry Volume: 27 Issue: 11 Pages: 2181-2186
  • DOI: 10.1016/j.bmc.2019.04.015
  • Peer Reviewed
• [Journal Article] Basal expression of interferon regulatory factor 1 drives intrinsic hepatocyte resistance to multiple RNA viruses (2019)
  • Author(s): Yamane D, Feng H, Rivera-Serrano EE, Selitsky SR, Hirai-Yuki A, Das A, McKnight KL, Misumi I, Hensley L, Lovell W, González-López O, Suzuki R, Matsuda M, Nakanishi H, Ohto-Nakanishi T, Hishiki T, Wauthier E, Oikawa T, Morita K, Reid LM, Sethupathy P, Kohara M, Whitmire JK, Lemon SM
  • Journal Title: Nature Microbiology Volume: 印刷中 Issue: 7 Pages: 1096-1104
  • DOI: 10.1038/s41564-019-0425-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Stearoyl-CoA desaturase-1 is required for flavivirus RNA replication (2019)
  • Author(s): Hishiki Takayuki、Kato Fumihiro、Nio Yasunori、Watanabe Satoru、Wen Tan Nicole Wei、Yamane Daisuke、Miyazaki Yasuyuki、Lin Chun-Chieh、Suzuki Rieko、Tajima Shigeru、Lim Chang-Kweng、Saijo Masayuki、Hijikata Makoto、Vasudevan Subhash G.、Takasaki Tomohiko
  • Journal Title: Antiviral Research Volume: 165 Pages: 42-46
  • DOI: 10.1016/j.antiviral.2019.03.002
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Apolipoprotein E is an HIV-1-inducible inhibitor of viral production and infectivity in macrophages (2018)
  • Author(s): Siddiqui Rokeya、Suzu Shinya、Ueno Mikinori、Nasser Hesham、Koba Ryota、Bhuyan Farzana、Noyori Osamu、Hamidi Sofiane、Sheng Guojun、Yasuda-Inoue Mariko、Hishiki Takayuki、Sukegawa Sayaka、Miyagi Eri、Strebel Klaus、Matsushita Shuzo、Shimotohno Kunitada、Ariumi Yasuo
  • Journal Title: PLOS Pathogens Volume: 14 Issue: 11 Pages: 1007372-1007372
  • DOI: 10.1371/journal.ppat.1007372
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] An estrogen antagonist, cyclofenil, has anti-dengue-virus activity (2018)
  • Author(s): Tohma Daiki、Tajima Shigeru、Kato Fumihiro、Sato Hirotaka、Kakisaka Michinori、Hishiki Takayuki、Kataoka Michiyo、Takeyama Haruko、Lim Chang-Kweng、Aida Yoko、Saijo Masayuki
  • Journal Title: Archives of Virology Volume: 164 Issue: 1 Pages: 225-234
  • DOI: 10.1007/s00705-018-4079-0
  • Peer Reviewed
• [Journal Article] Multiple antiviral activities of the antimalarial and anti-hepatitis C drug candidates N-89 and N-251 (2018)
  • Author(s): Ueda Youki、Gu Weilin、Dansako Hiromichi、Kim Hye-Sook、Yoshizaki Sayaka、Okumura Nobuaki、Ishikawa Tomohiro、Nishitsuji Hironori、Kato Fumihiro、Hishiki Takayuki、Satoh Shinya、Ishii Koji、Masuda Michiaki、Shimotohno Kunitada、Ikeda Masanori、Kato Nobuyuki
  • Journal Title: Biochemistry and Biophysics Reports Volume: 15 Pages: 1-6
  • DOI: 10.1016/j.bbrep.2018.05.007
  • Peer Reviewed / Open Access
• [Journal Article] Evaluation of Macaca radiata as a non-human primate model of Dengue virus infection. (2018)
  • Author(s): Kato Fumihiro, Ishida Yuki, Kawakami Akihiko, Takasaki Tomohiko, Saijo Masayuki, Miura Tomoyuki, Hishiki Takayuki.
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 3421-3421
  • DOI: 10.1038/s41598-018-21582-9
  • NAID: 120006523833
  • Peer Reviewed / Open Access
• [Journal Article] Hirsutine, an Indole Alkaloid of Uncaria rhynchophylla, Inhibits Late Step in Dengue Virus Lifecycle (2017)
  • Author(s): Hishiki Takayuki、Kato Fumihiro、Tajima Shigeru、Toume Kazufumi、Umezaki Masahito、Takasaki Tomohiko、Miura Tomoyuki
  • Journal Title: Frontiers in Microbiology Volume: 8 Pages: 1674-1674
  • DOI: 10.3389/fmicb.2017.01674
  • Peer Reviewed / Open Access
• [Presentation] Development of zika virus replicon cells expressing secretory luciferase (2019)
  • Author(s): 日紫喜隆行、加藤文博、鈴木理恵子、田島茂、林昌宏、西條政幸、高崎智彦
  • Organizer: 第67回日本ウイルス学会学術集会
• [Presentation] 分泌型ルシフェラーゼを有するジカウイルス一過性レプリコンの構築 (2018)
  • Author(s): 日紫喜隆行、加藤文博、田島茂、林昌宏、西條政幸、高崎智彦
  • Organizer: 第66回日本ウイルス学会学術集会
• [Presentation] 不飽和脂肪酸合成酵素阻害剤によるデングウイルス複製抑制機構の解析 (2017)
  • Author(s): 日紫喜隆行、加藤文博、仁尾泰徳、宮崎恭行、田島茂、土方誠、高崎智彦
  • Organizer: 第65回 日本ウイルス学会学術集会
• [Presentation] デングウイルス感染症 (2017)
  • Author(s): 日紫喜隆行
  • Organizer: 第160回 日本獣医学会学術集会
  • Invited
• [Presentation] Development of dengue virus replicon cells expressing secretory luciferase (2017)
  • Author(s): Takayuki Hishiki, Fumihiro Kato, Shigeru Tajima, Tomohiko Takasaki
  • Organizer: 2nd International Meeting on Arboviruses and their Vectors
  • Int'l Joint Research
• [Presentation] 分泌型ルシフェラーゼ発現レプリコン細胞を用いた抗デングウイルス化合物の探索 (2017)
  • Author(s): 日紫喜隆行、加藤文博、田島茂、高崎智彦
  • Organizer: 第52回 日本脳炎ウイルス生態学研究会