Discovery and development of agents for chronic hepatitis C from marine natural products

• Project/Area Number: 25460985
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: University of Yamanashi
• Principal Investigator: YAMASHITA Atsuya 山梨大学, 総合研究部, 助教 (00334871)
• Co-Investigator(Renkei-kenkyūsha): ENOMOTO Nobuyuki 山梨大学, 総合研究部, 教授 (20251530) ; MORIISHI Koji 山梨大学, 総合研究部, 教授 (90260273)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); 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: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: C型肝炎ウイルス / 治療薬 / 海洋生物 / 抗ウイルス剤 / HCV / 治療薬開発 / 創薬

Outline of Final Research Achievements

We focused on pharmacologically active component from marine organisms for the development of novel anti hepatitis C virus agent. Thus, we screened extracts of marine organisms by using HCV replicon system and showed that the extract from Amphimedon sp. inhibits HCV replication by suppressing viral helicase and protease activities. In this study, we attempted to purify and identify the active component of Amphimedon sp., but not purify and identify it.　Additionally, we established a cell-based screening system in order to identify compounds inhibiting the HCV NS2/3 protease activity. We screened extracts of marine organisms by using this system, but not identify extracts of marine organisms inhibiting the HCV NS2/3 protease activity.

Research Products

• [Journal Article] Identification of hydroxyanthraquinones as novel inhibitors of hepatitis C virus NS3 helicase (2015)
  • Author(s): Atsushi Furuta, Masayoshi Tsubuki, Miduki Endoh, Tatsuki Miyamoto, Junichi Tanaka, Kazi Abdus Salam, Nobuyoshi Akimitsu, Hidenori Tani, Atsuya Yamashita, Kohji Moriishi, Masamichi Nakakoshi, Yuji Sekiguchi, Satoshi Tsuneda, Naohiro Noda
  • Journal Title: Int H Mol Sci Volume: 16 Pages: 18439-18453
  • DOI: 10.3390/ijms160818439
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Deep sequencing and phylogenetic analysis of variants resistant to interferon-based protease inhibitor therapy in chronic hepatitis induced by genotype 1b hepatitis C virus. (2015)
  • Author(s): Sato M, Maekawa S, Komatsu N, Tatsumi A, Miura M, Muraoka M, Suzuki Y, Amemiya F, Takano S, Fukasawa M, Nakayama Y, Yamaguchi T, Uetake T, Inoue T, Sato T, Sakamoto M, Yamashita A, Moriishi K, Enomoto N.
  • Journal Title: Journal of Virology Volume: 89(11) Pages: 6105-16
  • DOI: 10.1128/jvi.03127-14
  • Peer Reviewed / Open Access
• [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
  • Journal Title: Mar Drugs Volume: 13 Pages: 6759-6773
  • DOI: 10.3390/md13116759
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Involvement of FKBP6 in hepatitis C virus replication (2015)
  • Author(s): Kasai H, Kawakami Y, Yokoe H, Yoshimura K, Matsuda M, Yasumoto J, Maekawa S, Yamashita A, Tanaka T, Ikeda M, Kato N, Okamoto T, Matsuura Y, Sakamoto N, Enomoto N, Takeda S, Fujii H, Tsubuki M, Kusunoki M, Moriishi K.
  • Journal Title: Scientific Reports Volume: 5 Pages: 16699-16699
  • DOI: 10.1038/srep16699
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [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.
  • Journal Title: Scientific Reports Volume: 5 Pages: 17047-17047
  • DOI: 10.1038/srep17047
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Hallmarks of hepatitis C virus in equine hepacivirus. (2015)
  • Author(s): Tanaka T, Kasai H, Yamashita A, Okuyama-Dobashi K, Yasumoto J, Maekawa S, Enomoto N, Okamoto T, Matsuura Y, Morimatsu M, Manabe N, Ochiai K, Yamashita K, Moriishi K.
  • Journal Title: Journal of Virology Volume: 88(22) Pages: 13352-13366
  • DOI: 10.1128/jvi.02280-14
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] PBDE: Structure-activity studies for the inhibition of hepatitis C virus NS3 helicase (2014)
  • Author(s): Salam KA, Furuta A, Noda N, Tsuneda S, Sekiguchi Y, Yamashita A, Moriishi K, Nakakoshi M, Tani H, Roy SR, Tanaka J, Tsubuki M, Akimitsu N
  • Journal Title: Molecules Volume: 19 Pages: 4006-4020
  • DOI: 10.3390/molecules19044006
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Identification and biochemical characterization of halisulfate 3 and suvanine as novel inhibitors of hepatitis C virus NS3 helicase from a marine sponge. (2014)
  • Author(s): Furuta A, Salam KA, Hermawan I, Akimitsu N, Tanaka J, Tani H, Yamashita A, Moriishi K, Nakakoshi M, Tsubuki M, Peng PW, Suzuki Y, Yamamoto N, Sekiguchi Y, Tsuneda S, Noda N
  • Journal Title: Marine Drugs Volume: 12 Pages: 462-476
  • DOI: 10.3390/md12010462
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Cholesterol sulfate as a potential inhibitor of hepatitis C virus NS3 helicase. (2014)
  • Author(s): Yamashita, A.; Moriishi, K.; Tsubuki, M.; Nakakoshi, M.; Sekiguchi, Y.; Tsuneda, S.; Noda, N
  • Journal Title: Journal of Enzyme Inhibition and Medicinal Chemistry Volume: 28 Pages: 223-229
  • DOI: 10.3109/14756366.2013.766607
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Inhibitory Effects of Caffeic Acid Phenethyl Ester Derivatives on Replication of Hepatitis C Virus (2014)
  • Author(s): Maekawa S, Enomoto N
  • Journal Title: PLoS ONE Volume: 49(1) Pages: 163-164
  • DOI: 10.1371/journal.pone.0082299
  • Peer Reviewed
• [Journal Article] Deep-Sequencing Analysis of the Association between the Quasispecies Nature of the Hepatitis C Virus Core Region and Disease Progression. (2013)
  • Author(s): Miura M, Maekawa S, Takano S, Komatsu N, Tatsumi A, Asakawa Y, Shindo K, Amemiya F, Nakayama Y, Inoue T, Sakamoto M, Yamashita A, Moriishi K, Enomoto N.
  • Journal Title: J. Virol. Volume: 87(23) Pages: 12541-12551
  • DOI: 10.1128/jvi.00826-13
  • Peer Reviewed
• [Journal Article] IL28B(IFN-λ3)and IFN-α synergisitically inhibit HCV replication. (2013)
  • Author(s): Shindo H
  • Journal Title: J Viral hepatitis. Volume: 20 Pages: 281-289
  • DOI: 10.1111/j.1365-2893.2012.01649.x
  • Peer Reviewed
• [Journal Article] Psammaplin A inhibits hepatitis C virus NS3 helicase. (2013)
  • Author(s): Salam, K.A.; Furuta, A.; Noda, N.; Tsuneda, S.; Sekiguchi, Y.; Yamashita, A.; Moriishi, K.; Nakakoshi, M.; Tsubuki, M.; Tani, H.; Tanaka, J.; Akimitsu, N
  • Journal Title: J Nat Med. Volume: 67 Pages: 765-772
  • DOI: 10.1007/s11418-013-0742-7
  • NAID: 40019787969
  • Peer Reviewed
• [Journal Article] Serum RANTES level influences the response to pegylated interferon and ribavirin therapy in chronic hepatitis C (2013)
  • Author(s): Komase K, Maekawa S, Miura M, Sueki R, Kadokura M, Shindo H, Shindo K, Amemiya F, Nakayama Y, Inoue T, Sakamoto M, Yamashita A, Moriishi K, Enomoto N
  • Journal Title: Hepatol Res. Volume: 43(8) Pages: 865-875
  • DOI: 10.1111/hepr.12032
  • NAID: 10031194591
  • Peer Reviewed
• [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: 第38回日本分子生物学会年会 第88回日本生化学会大会 合同大会
  • Place of Presentation: 神戸ポートアイランド（兵庫県神戸市）
  • Year and Date: 2015-12-01
• [Presentation] B型肝炎ウイルスコアプロモーター転写阻害剤のハイスループットスクリーニング. (2015)
  • Author(s): 古谷祐, 森田直子, 佐藤裕美, 山下篤哉, 森石恆司, 小嶋聡一
  • Organizer: 第38回日本分子生物学会年会 第88回日本生化学会大会 合同大会
  • Place of Presentation: 神戸ポートアイランド（兵庫県神戸市）
  • Year and Date: 2015-12-01
• [Presentation] Metachromin A, sesquiterpene from marine sponge Dactylospongia metachromia, exerts anti-HBV activity via inhibition of HBV core promoter. (2015)
  • Author(s): Atsuya Yamashita, Tomohisa Tanaka, Kaori Okuyama-Dobashi, Hirotake Kasai, Koichi Watashi, Takaji Wakita, Masaaki Toyama, Masanori Baba, Kohji Moriishi
  • Organizer: 第63回日本ウイルス学会学術集会
  • Place of Presentation: 福岡国際会議場（福岡県福岡市）
  • Year and Date: 2015-11-22
• [Presentation] Hepatitis B virus downregulates expression of CIDE-B and CIDE-C and impairs lipid droplet growth. (2015)
  • Author(s): Jun Yasumoto， Hirotake Kasai， Tomohisa Tanaka， Koichi Watashi，Takaji Wakita，Atsuya Yamashita，Kaori Dobashi-Okuyama1，Kohji Moriishi
  • Organizer: 第63回日本ウイルス学会学術集会
  • Place of Presentation: 福岡国際会議場（福岡県福岡市）
  • Year and Date: 2015-11-22
• [Presentation] Inhibitory effect of tyrphostin derivative HD-31 on hepatitis C virus replication via regulation of reactive oxygen species production. (2015)
  • Author(s): Ryota Amano，Atsuya Yamashita，Hirotake Kasai，Kohji Moriishi
  • Organizer: 第63回日本ウイルス学会学術集会
  • Place of Presentation: 福岡国際会議場（福岡県福岡市）
  • Year and Date: 2015-11-22
• [Presentation] Characterization of the IRES activity in equine hepacivirus 5’UTR. (2015)
  • Author(s): Tomohisa Tanaka，Chen Wenjia，Teruhime Otoguro，Hirotake Kasai，Atsuya Yamashita, Kohji Moriishi
  • Organizer: 第63回日本ウイルス学会学術集会
  • Place of Presentation: 福岡国際会議場（福岡県福岡市）
  • Year and Date: 2015-11-22
• [Presentation] Screening of presenilin inhibitors for identification of anti-HCV compound. (2015)
  • Author(s): Teruhime Otoguro，Tomohisa Tanaka，Hirotake Kasai，Atsuya Yamashita，Kohji Moriishi
  • Organizer: 第63回日本ウイルス学会学術集会
  • Place of Presentation: 福岡国際会議場（福岡県福岡市）
  • Year and Date: 2015-11-22
• [Presentation] カイメン由来化合物metachromin A及びその類縁化合物の抗HBV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: 第25回抗ウイルス療法学会
  • Place of Presentation: 国立感染症研究所（東京都新宿区）
  • Year and Date: 2015-05-22
• [Presentation] 海洋生物抽出物ライブラリーソースからのB型肝炎ウイルス転写活性抑制化合物の探索 (2014)
  • Author(s): 山下篤哉、藤本雄介、田中智久、葛西宏威、児玉栄一、渡士幸一、脇田隆字、前川伸哉、
  • Organizer: 第62回日本ウイルス学会
  • Place of Presentation: パシフィコ横浜 (神奈川県横浜市）
  • Year and Date: 2014-11-10 – 2014-11-12
• [Presentation] 海洋生物抽出物ライブラリーソースとしたB型肝炎ウイルス転写活性抑制化合物の探索 (2014)
  • Author(s): 山下篤哉、藤本雄介、児玉栄一、田中智久、葛西宏威、前川伸哉、榎本信幸、田中 淳一、
  • Organizer: 第24回抗ウイルス療法研究会
  • Place of Presentation: ハイランドリゾートホテル （山梨県富士吉田市）
  • Year and Date: 2014-05-07 – 2014-05-09
• [Presentation] カフェ酸類縁化合物によるHCVゲノム複製阻害 (2014)
  • Author(s): 山下篤哉、沈暉、天野稜大、中越雅道、横江弘雅、須藤誠士、田中智久、葛西宏威、進藤浩子、
  • Organizer: 第24回抗ウイルス療法研究会
  • Place of Presentation: ハイランドリゾートホテル （山梨県富士吉田市）
  • Year and Date: 2014-05-07 – 2014-05-09
• [Presentation] 海綿Amphimedon sp.抽出画分のHCVゲノム複製阻害効果とその作用機序 (2013)
  • Author(s): 山下篤哉、藤本雄介、Kazi Abdus Salam、古田 篤史、谷 英典、前川 信哉、榎本 信幸、中越雅道、津吹政可、関口勇地、常田聡、秋光信佳、野田尚宏、田中淳一、森石恆司
  • Organizer: 第23回抗ウイルス療法研究会総会
  • Place of Presentation: リーガロイヤルホテル東京（東京都新宿区）
• [Presentation] Caffeic acid phenethyl esterとその類縁化合物によるHCVゲノム複製阻害 (2013)
  • Author(s): 山下篤哉、沈暉、田中智久、葛西宏威、森石恆司
  • Organizer: 第61回日本ウイルス学会学術集会
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市中央区）
• [Presentation] Tyrphostinとその類縁化合物によるC型肝炎ウイルス複製阻害 (2013)
  • Author(s): 天野稜大、山下篤哉、葛西宏威、田中智久、前川伸哉、榎本信幸、津吹政可、森石恆司
  • Organizer: 第36会日本分子生物学会年会
  • Place of Presentation: 神戸ポートアイランド（兵庫県神戸市中央区）
• [Remarks] 山梨大学医学部 微生物学講座
  • URL: http://www.med.yamanashi.ac.jp/clinical_basic/microbio/Microbiology_Yamanashi_Uni_Japanese/Home.html
• [Remarks] 山梨大学 研究者総覧
  • URL: http://erdb.yamanashi.ac.jp/rdb/A_DispInfo.Scholar/4_5_4/E88A6696C4043E75.html
• [Remarks] 山梨大学 研究者総覧
  • URL: http://erdb.yamanashi.ac.jp/rdb/A_Index.Main