Analyses of effects of novel anti-herpesvirus compounds identified in screening on viral replication and gene expression

• Project/Area Number: 25460578
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Virology
• Research Institution: Gifu Pharmaceutical University
• Principal Investigator: Inoue Naoki 岐阜薬科大学, 薬学部, 教授 (90183186)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: サイトメガロウイルス / 水痘帯状疱疹ウイルス / 抗ウイルス薬 / 薬剤耐性 / カプシド / 転写活性化因子

Outline of Final Research Achievements

Previously we identified a few anti-cytomegalovirus (CMV) and anti-varicella zoster virus (VZV) compounds, respectively, by screening of a 9600 chemical compound library with reporter cell lines that can detect each virus quickly.　In this study, we analyzed effects of the identified compounds on viral DNA replication and gene expression as well as on viral growth properties, and found the followings: 1) anti-VZV compound 45B5 targets the portal protein encoded by ORF54 and probably inhibits the process of viral DNA injection into the nuclei. 2) anti-VZV and -CMV compound 133G4 inhibits the transactivation functions of immediate-early proteins encoded by VZV, CMV, and herpes simplex virus, probably through a host factor. 3) 35C10 inhibits a process between the penetration of virus into cells and the expression of immediate-early protein.

Research Products

• [Journal Article] An ex vivo culture model for placental cytomegalovirus infection using slices of guinea pig placental tissue. (2016)
  • Author(s): Yamada S, Katano H, Sato Y, Fukuchi S, Hashimoto K, Inoue N
  • Journal Title: Placenta Volume: 37 Pages: 85-88
  • DOI: 10.1016/j.placenta.2015.10.016
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Neurological outcomes in symptomatic congenital cytomegalovirus-infected infants after introduction of newborn urine screening and antiviral treatment. (2016)
  • Author(s): Nishida K, Morioka I, Nakamachi Y, Kobayashi Y, Imanishi T, Kawano S, Iwatani S, Koda T, Deguchi M, Tanimura K, Yamashita D, Nibu KI, Funakoshi T, Ohashi M, Inoue N, Iijima K, Yamada H.
  • Journal Title: Brain & Dev Volume: 38 Pages: 209-216
  • Peer Reviewed
• [Journal Article] 新しい抗ヘルペスウイルス薬 (2015)
  • Author(s): 井上直樹、安井瑠香、馬島龍一、山田晃平
  • Journal Title: 臨床とウイルス Volume: 43 Pages: 285-295
• [Journal Article] Low total IgM values and high cytomegalovirus loads in the blood of newborns with symptomatic congenital cytomegalovirus infection. (2015)
  • Author(s): Kobayashi Y, Morioka I, Koda T, Nakamachi Y, Okazaki Y, Noguchi Y, Ogi M, Chikahira M, Tanimura K, Ebina Y, Funakoshi T, Ohashi M, Iijima K, Inoue N, Kawano S, Yamada H
  • Journal Title: J Perinatal Med Volume: 43 Issue: 2 Pages: 239-243
  • DOI: 10.1515/jpm-2014-0071
  • NAID: 120005740370
  • Peer Reviewed
• [Journal Article] Evidence for human herpesvirus-6B infection of regulatory T-cells in acute systemic lymphadenitis in an immunocompetent adult with the drug reaction with eosinophilia and systemic symptoms syndrome: A case report. (2014)
  • Author(s): Mine S, Suzuki K, Sato Y, Fukumoto H, Kataoka M, Inoue N, Ohbayashi C, Hasegawa H, Sata T, Fukayama M,Katano H
  • Journal Title: J Clin Virol Volume: 61 Issue: 3 Pages: 448-452
  • DOI: 10.1016/j.jcv.2014.08.025
  • Peer Reviewed
• [Journal Article] Aberrant fetal macrophage/microglial reaction to cytomegalovirus infection. (2014)
  • Author(s): akiko Sakao-Suzuki Hideya Kawasaki Taisuke Akamatsu, Shiori Meguro, Hiroaki Miyajima Toshihide Iwashita, Yoshihiro Tsutsui, Naoki Inoue5 & Isao Kosugi.
  • Journal Title: Annals of Clinical and Translational Neurology Volume: 1(8) Issue: 8 Pages: 570-588
  • DOI: 10.1002/acn3.88
  • Peer Reviewed / Open Access
• [Journal Article] The presence of antibodies against the AD2 epitope of cytomegalovirus glycoprotein B is associated with acute rejection after renal transplantation. (2014)
  • Author(s): Ishibashi K, Tokumoto T, Shirakawa H, Oguro T, Yanagida T, Takahashi N, Nomiya M, Haga N, Aikawa K, Tanabe K, Inoue N, Kojima Y, Suzutani T
  • Journal Title: Microbiol Immunol Volume: 58 Issue: 1 Pages: 72-75
  • DOI: 10.1111/1348-0421.12112
  • Peer Reviewed
• [Journal Article] Guinea pig cytomegalovirus GP129/131/133, homologs of human cytomegalovirus UL128/130/131A, are required for infection of monocytes and macrophages (2014)
  • Author(s): Yamada S, Fukuchi S, Hashimoto K, Fukui Y, Tsuda M, Kataoka M, Katano H, Inoue N
  • Journal Title: J Gen Virol Volume: 95 Issue: 6 Pages: 1376-1382
  • DOI: 10.1099/vir.0.064527-0
  • Peer Reviewed
• [Journal Article] Idiopathic intrauterine growth restriction caused by cytomegalovirus infection and associated placental pathology. (2014)
  • Author(s): Pereira L, Petitt M, Fong A, Tsuge M, Tabata T, Fang-Hoover J, Maidji E, Zydek M, Zhou Y, Inoue N, Logahvi S, Pepkowitz S, Ogunyemi D
  • Journal Title: J Infec Dis Volume: 209 Issue: 10 Pages: 1573-1584
  • DOI: 10.1093/infdis/jiu019
  • Peer Reviewed
• [Journal Article] The IgG avidity value for the prediction of congenital cytomegalovirus infection in a prospective cohort study (2014)
  • Author(s): Ebina Y, Minematsu T, Sonoyama A, Morioka I, Inoue N, Tairaku S, Nagamata S, Tanimura K,Morizane M, Deguchi M, Yamada H
  • Journal Title: J Perinat Med Volume: - Issue: 6 Pages: 755-759
  • DOI: 10.1515/jpm-2013-0333
  • Peer Reviewed
• [Journal Article] Molecular and virological evidence of viral activation from chromosomally integrated human herpesvirus 6A in a patient with X-linked severe combined immunodeficiency (2014)
  • Author(s): Endo A, Watanabe K, Ohye T, Suzuki K, Matsubara T, Shimizu N, Kurahashi H, Yoshikawa T, Katano H, Inoue N, Imai K, Takagi M, Morio T, Mizutani S
  • Journal Title: Clin Infect Dis Volume: 59 Issue: 4 Pages: 545-548
  • DOI: 10.1093/cid/ciu323
  • Peer Reviewed / Open Access
• [Journal Article] The highly conserved human cytomegalovirus UL136 ORF generates multiple Golgi-localizing protein isoforms through differential translation initiation (2014)
  • Author(s): Liao H, Lee JH, Kondo R, Katata M, Imadome K, Miyado K, Inoue N, Fujiwara S, Nakamura H
  • Journal Title: Virus Res Volume: 179 Pages: 241-6
  • DOI: 10.1016/j.virusres.2013.11.002
  • Peer Reviewed
• [Journal Article] Unusually extensive disseminated herpes zoster with multiple ulcer formation in a methotrexate-treated rheumatoid arthritis patient. (2014)
  • Author(s): Kakuta R, Okata U, Funakoshi T, Fujio Y, Inoue N, Takahashi S, Amagai M, Ohyama M.
  • Journal Title: J. Dermatology Volume: 41 Issue: 2 Pages: 181-182
  • DOI: 10.1111/1346-8138.12377
  • Peer Reviewed
• [Journal Article] Quantitative Evaluation of Ventricular Dilatation using Computed Tomography in Infants with Congenital Cytomegalovirus Infection. (2013)
  • Author(s): Matsuo K
  • Journal Title: Brain & Development. Volume: in press Issue: 1 Pages: 10-15
  • DOI: 10.1016/j.braindev.2012.12.009
  • Peer Reviewed
• [Journal Article] Effects of immunization of pregnant guinea pigs with guinea pig cytomegalovirus glycoprotein B on viral spread in the placenta. (2013)
  • Author(s): Hashimoto K, Yamada S, Katano H, Fukuchi S, Sato Y, Kato M, Yamaguchi T, Moriishi K, Inoue N
  • Journal Title: Vaccine Volume: 31 Issue: 31 Pages: 3199-205
  • DOI: 10.1016/j.vaccine.2013.04.078
  • Peer Reviewed
• [Journal Article] Cytomegalovirus (CMV) glycoprotein H-based serological analysis in Japanese healthy pregnant women, and in neonates with congenital CMV infection and their mothers. (2013)
  • Author(s): 14. Ikuta K, Minematsu T, Inoue N, Kubo T, Asano K, Ishibashi K, Imamura T, Nakai H, Yoshikawa T, Moriuchi H, Fujiwara S, Koyano S, Suzutani T
  • Journal Title: J Clin Virol Volume: 58 Issue: 2 Pages: 474-478
  • DOI: 10.1016/j.jcv.2013.07.004
  • Peer Reviewed
• [Journal Article] Human cytomegalovirus induces apoptosis in neural stem/progenitor cells derived from induced pluripotent stem cells by generating mitochondrial dysfunction and endoplasmic reticulum stress (2013)
  • Author(s): Nakamura H, Imadome K, et al.(他10名)
  • Journal Title: Herpesviridae Volume: 4(1) Issue: 1 Pages: 2-2
  • DOI: 10.1186/2042-4280-4-2
  • Peer Reviewed
• [Journal Article] Polymorphisms in TLR-2 are associated with congenital cytomegalovirus (CMV) infection, but not with congenital CMV disease (2013)
  • Author(s): Taniguchi R, Koyano S, Suzutani T, Goishi K, Ito Y, Morioka I, Oka A, Nakamura H, Yamada H,Igarashi T, Inoue N
  • Journal Title: Int J Infect Dis Volume: 17 Issue: 12 Pages: 1092-1097
  • DOI: 10.1016/j.ijid.2013.06.004
  • Peer Reviewed
• [Journal Article] Detection of human herpesviruses in the cerebrospinal fluid from patients diagnosed with or suspected of having progressive multifocal leukoencephalopathy (2013)
  • Author(s): K. Nakamichi, N. Inoue, T. Shimokawa, I. Kurane, C.K. Lim, M. Saijo
  • Journal Title: BMC Neurology Volume: 13(200) Issue: 1 Pages: 200-200
  • DOI: 10.1186/1471-2377-13-200
  • Peer Reviewed
• [Presentation] 水痘帯状疱疹ウイルスportalタンパクを標的とする新規抗ウイルス化合物の同定と作用機序の解析 (2016)
  • Author(s): 安井瑠香、井上直樹
  • Organizer: 日本薬学会第136年会
  • Place of Presentation: 横浜
  • Year and Date: 2016-03-27
• [Presentation] HHV6B の制御性 T 細胞への感染が証明された DRESS 症候群の一剖検例 (2014)
  • Author(s): 峰宗太郎、鈴木高祐、佐藤由子、福本瞳、井上直樹、片岡紀代、大林千穂、長谷川秀樹、佐多徹太郎、深山正久、片野晴隆
  • Organizer: 第62回日本ウイルス学会学術集会
  • Place of Presentation: パシフィコ横浜会議センター（横浜市）
  • Year and Date: 2014-11-10 – 2014-11-12
• [Presentation] 新規作用メカニズムによるEHV-1感染症治療薬候補化合物の探索 (2014)
  • Author(s): 岡田彩加、安井瑠香、井上直樹、大屋賢司、福士秀人
  • Organizer: 第157回日本獣医学会学術集会
  • Place of Presentation: 北海道大学（札幌市）
  • Year and Date: 2014-09-09 – 2014-09-12
• [Presentation] The two wheels for infection control of VZV diseases: quality control of vaccine products and development of anti-VZV compounds (2014)
  • Author(s): Inoue N
  • Organizer: The 39th International Herpesvirus Workshop
  • Place of Presentation: 神戸国際展示場（神戸市）
  • Year and Date: 2014-07-23
  • Invited
• [Presentation] A single nucleotide polymorphism in the NKG2D gene is associated with clinical outcome of congenital cytomegalovirus infection at birth. (2014)
  • Author(s): Taniguchi R, Koyano S, Suzutani T, Goishi K, Ito Y, Morioka I, Nakamura H, Yamada H, Oka A, Inoue N
  • Organizer: The 39th International Herpesvirus Workshop
  • Place of Presentation: 神戸国際展示場（神戸市）
  • Year and Date: 2014-07-19 – 2014-07-23
• [Presentation] Guinea Pig CMV GP129/131/133, Homologs of HCMV UL128/130/131A, are Required for Entry into Macrophages but not into Fibroblast and Epithelial cells (2013)
  • Author(s): Kaede Hashimoto, Saki Fukuchi, Souichi Yamada, Yoshiko Fukui, Mihoko Tsuda, Michiyo Kataoka, Harutaka Katano, ○Naoki Inoue
  • Organizer: 第38回国際ヘルペスウイルスワークショップ
  • Place of Presentation: 米国Grand Rapids
• [Remarks] 岐阜薬科大学 生命薬学大講座 感染制御学研究室
  • URL: http://sv1.gifu-pu.ac.jp/lab/kansen/