High through anti-HBV drug screening by using reporter assay

• Project/Area Number: 19K08458
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Hokkaido University
• Principal Investigator: Suda Goki 北海道大学, 大学病院, 特任助教 (20447460)
• Co-Investigator(Kenkyū-buntansha): 坂本 直哉 北海道大学, 医学研究院, 教授 (10334418) ; 森川 賢一 北海道大学, 医学研究院, 准教授 (60384377)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: HBV / スクリーニング / drug screening / 創薬 / レポーター / 抗HBV薬 / 大規模スクリーニング / IFN / ハイスループット / ドラッグスクリーニング

Outline of Research at the Start

現在、B型肝炎ウイルス（HBV）に対する治療選択は核酸アナログとインターフェロン（IFN）に限定される。現在の新規薬剤開発のボトルネックは、適切なHBV感染培養系と簡便な大規模スクリーニング系の開発が十分でない事が一因となる。本研究では申請者らが明らかにしたHBVタンパクによるIFNシグナル阻害に着目した新規の抗HBV薬のレポーターアッセイを用いた大規模スクリーニング系を構築。同スクリーニング系を用いた検討にて複数の新規薬剤候補を同定可能であった。今研究では同スクリーニング系を用いて、更なる新規の抗HBV薬の同定、既存薬のrepositioning を目指す。

Outline of Final Research Achievements

We revealed that hepatitis B virus X protein inhibit IFN signaling pathway. We focused on these mechanisms, we established novel high-throughput screening system to find novel anti-HBV drug by using reporter assay system. In addition, we utilized “Hokdai library” which consisted of chemical library and existing drugs e.g. By using this novel system and drug library, we found several potential compounds which could suppress HBV replications.

Academic Significance and Societal Importance of the Research Achievements

B型肝炎ウイルス(HBV)は全世界で4億人の感染者が存在し、世界的な公衆衛生上の問題となる感染症である。一方で、現時点までに使用可能な抗HBV薬は核酸アナログとIFNのみであり、加えてこれらの薬剤ではHBVの排除は困難で、更なる抗HBV薬の開発は急務である。我々は、独自に開発したスクリーニング系と北海道大学が独自に有する薬剤、化合物を用いて複数の抗HBV薬候補を同定した。これらの薬剤は、既存薬と比してHBｓ抗原の低下効果が強く、臨床的治癒となるＨＢs抗原の消失が期待される薬剤候補であった。これらの、新規薬剤候補の臨床応用を目指す事によりHBV撲滅に向けた創薬基盤の萌芽となりうる。

Research Products

• [Journal Article] Changes in Serum Growth Factors during Lenvatinib Predict the Post Progressive Survival in Patients with Unresectable Hepatocellular Carcinoma (2022)
  • Author(s): Yang Zijian、Suda Goki、et al.,
  • Journal Title: Cancers Volume: 14 Issue: 1 Pages: 232-232
  • DOI: 10.3390/cancers14010232
  • Peer Reviewed / Open Access
• [Journal Article] Effect of switching from tenofovir disoproxil fumarate to tenofovir alafenamide on lipid profiles in patients with hepatitis B (2022)
  • Author(s): Suzuki Kazuharu、Suda Goki、Yamamoto Yoshiya、Abiko Satoshi、Kinoshita Kenji、Miyamoto Shuichi、Sugiura Ryo、Kimura Megumi、Maehara Osamu、Yamada Ren、Kitagataya Takashi、Shigesawa Taku、Ohara Masatsugu、Kawagishi Naoki、Nakai Masato、Sho Takuya、Natsuizaka Mitsuteru、Morikawa Kenichi、Ogawa Koji、Sakamoto Naoya
  • Journal Title: PLOS ONE Volume: 17 Issue: 1 Pages: 261760-261760
  • DOI: 10.1371/journal.pone.0261760
  • Peer Reviewed / Open Access
• [Journal Article] Liver-related events after direct-acting antiviral therapy in patients with hepatitis C virus-associated cirrhosis (2022)
  • Author(s): Tahata Y, Hikita H, Mochida S, Enomoto N, Kawada N, Kurosaki M, Ido A, Miki D, Yoshiji H, Takikawa Y, Sakamori R, Hiasa Y, Nakao K, Kato N, Ueno Y, Yatsuhashi H, Itoh Y, Tateishi R, Suda G, Takami T, Nakamoto Y, Asahina Y, et al.
  • Journal Title: Journal of Gastroenterology Volume: 57 Issue: 2 Pages: 120-132
  • DOI: 10.1007/s00535-021-01845-5
  • Peer Reviewed
• [Journal Article] Prediction of hepatocellular carcinoma using age and liver stiffness on transient elastography after hepatitis C virus eradication (2022)
  • Author(s): Nakai Masato、Yamamoto Yoshiya、Baba Masaru、Suda Goki、Kubo Akinori、Tokuchi Yoshimasa、Kitagataya Takashi、Yamada Ren、Shigesawa Taku、Suzuki Kazuharu、Nakamura Akihisa、Sho Takuya、Morikawa Kenichi、Ogawa Koji、Furuya Ken、Sakamoto Naoya
  • Journal Title: Scientific Reports Volume: 12 Issue: 1 Pages: 1449-1449
  • DOI: 10.1038/s41598-022-05492-5
  • Peer Reviewed / Open Access
• [Journal Article] Overestimated Renal Function in Patients with Liver Cirrhosis Predicts Poor Prognosis (2022)
  • Author(s): Yoshida Sonoe、Suda Goki、et al.,
  • Journal Title: Hepatology Research Volume: in press Issue: 7 Pages: 603-613
  • DOI: 10.1111/hepr.13765
  • Peer Reviewed
• [Journal Article] Changes in the estimated renal function after hepatitis C virus eradication with direct-acting antiviral agents: Impact of changes in skeletal muscle mass (2021)
  • Author(s): Tokuchi Y, Suda G, Kimura M, Maehara O, Kitagataya T, Ohara M, Yamada R, Shigesawa T, Suzuki K, Kawagishi N, Nakai M, Sho T, Natsuizaka M, Morikawa K, Ogawa K, Sakamoto N.
  • Journal Title: J Viral Hepat. Volume: in press Issue: 5 Pages: 755-763
  • DOI: 10.1111/jvh.13484
  • Peer Reviewed
• [Journal Article] Baseline serum angiopoietin-2 and VEGF levels predict the deterioration of the liver functional reserve during lenvatinib treatment for hepatocellular carcinoma (2021)
  • Author(s): Shigesawa T, Suda G, Kimura M, Maehara O, Tokuchi Y, Kubo A, Yamada R, Furuya K, Baba M, Kitagataya T, Suzuki K, Ohara M, Kawagishi N, Nakai M, Sho T, Natsuizaka M, Morikawa K, Ogawa K, Sakamoto N.
  • Journal Title: PLoS One Volume: 16(3) Issue: 3 Pages: e0247728-e0247728
  • DOI: 10.1371/journal.pone.0247728
  • Peer Reviewed / Open Access
• [Journal Article] Successful treatment by on-demand glecaprevir and pibrentasvir for hepatitis C flare during R-CHOP in patients with diffuse large B-cell lymphoma: a case report (2021)
  • Author(s): Umemura Machiko、Suda Goki、Tsukamoto Shihori、Ebata Ko、Takahash Shinjiro、Sasaki Takashi、Nakajima Sae、Hirata Koji、Ozasa Mariko、Takano Masatoshi、Katagiri Masaki、Sakamoto Naoya
  • Journal Title: BMC Infectious Diseases Volume: 21 Issue: 1
  • DOI: 10.1186/s12879-021-06091-x
  • Peer Reviewed
• [Journal Article] Baseline elevated serum angiopoietin-2 predicts long-term non-regression of liver fibrosis after direct-acting antiviral therapy for hepatitis C (2021)
  • Author(s): Kawagishi Naoki、Suda Goki、Kimura Megumi、Maehara Osamu、Yamada Ren、Tokuchi Yoshimasa、Kubo Akinori、Kitagataya Takashi、Shigesawa Taku、Suzuki Kazuharu、Ohara Masatsugu、Nakai Masato、Sho Takuya、Natsuizaka Mitsuteru、Morikawa Kenichi、Ogawa Koji、Kudo Yusuke、Nishida Mutsumi、Sakamoto Naoya
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 9207-9207
  • DOI: 10.1038/s41598-021-88632-7
  • Peer Reviewed / Open Access
• [Journal Article] FGFR2 maintains cancer cell differentiation via AKT signaling in esophageal squamous cell carcinoma (2021)
  • Author(s): Maehara Osamu、Suda Goki、Natsuizaka Mitsuteru、Shigesawa Taku、Kanbe Gouki、Kimura Megumi、Sugiyama Masaya、Mizokami Masashi、Nakai Masato、Sho Takuya、Morikawa Kenichi、Ogawa Koji、Ohashi Shinya、Kagawa Shingo、Kinugasa Hideaki、Naganuma Seiji、Okubo Naoto、Ohnishi Shunsuke、Takeda Hiroshi、Sakamoto Naoya
  • Journal Title: Cancer Biology & Therapy Volume: 22 Issue: 5-6 Pages: 372-380
  • DOI: 10.1080/15384047.2021.1939638
  • Peer Reviewed
• [Journal Article] Early response and safety of atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma in patients who do not meet IMbrave150 eligibility criteria (2021)
  • Author(s): Sho Takuya、Suda Goki、et al.,
  • Journal Title: Hepatology Research Volume: 51 Issue: 9 Pages: 979-989
  • DOI: 10.1111/hepr.13693
  • Peer Reviewed
• [Journal Article] Characteristics and Lenvatinib Treatment Response of Unresectable Hepatocellular Carcinoma with Iso-High Intensity in the Hepatobiliary Phase of EOB-MRI (2021)
  • Author(s): Kubo Akinori、Suda Goki、Kimura Megumi、Maehara Osamu、Tokuchi Yoshimasa、Kitagataya Takashi、Ohara Masatsugu、Yamada Ren、Shigesawa Taku、Suzuki Kazuharu、Kawagishi Naoki、Nakai Masato、Sho Takuya、Natsuizaka Mitsuteru、Morikawa Kenichi、Ogawa Koji、Ohnishi Shunsuke、Sakamoto Naoya
  • Journal Title: Cancers Volume: 13 Issue: 14 Pages: 3633-3633
  • DOI: 10.3390/cancers13143633
  • Peer Reviewed / Open Access
• [Journal Article] Frequency and Characteristics of Overestimated Renal Function in Japanese Patients with Chronic Liver Disease and Its Relation to Sarcopenia (2021)
  • Author(s): Yoshida Sonoe、Suda Goki、et al.,
  • Journal Title: Nutrients Volume: 13 Issue: 7 Pages: 2415-2415
  • DOI: 10.3390/nu13072415
  • Peer Reviewed / Open Access
• [Journal Article] Possible correlation between increased serum free carnitine levels and increased skeletal muscle mass following HCV eradication by direct acting antivirals (2021)
  • Author(s): Tokuchi Yoshimasa、Suda Goki、et al.,
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 16616-16616
  • DOI: 10.1038/s41598-021-96203-z
  • Peer Reviewed / Open Access
• [Journal Article] Genomic profiling of intestinal/mixed‐type superficial non‐ampullary duodenal epithelial tumors (2021)
  • Author(s): Miyamoto Shuichi、Suda Goki、Ishikawa Marin、Hayashi Hideyuki、Nimura Satoshi、Matsuno Yoshihiro、Mori Ryo、Tanishima Shigeki、Kudo Takahiko、Takagi Tomofumi、Yamamoto Yoshiya、Ono Shoko、Shimizu Yuichi、Sakamoto Naoya
  • Journal Title: JGH Open Volume: 5 Issue: 9 Pages: 1071-1077
  • DOI: 10.1002/jgh3.12632
  • Peer Reviewed
• [Journal Article] Nonalcoholic steatohepatitis in hepatocarcinoma: new insights about its prognostic role in patients treated with lenvatinib (2021)
  • Author(s): Rimini M.、Kudo M.、Tada T.、Shigeo S.、Kang W.、Suda G.、et al.,
  • Journal Title: ESMO Open Volume: 6 Issue: 6 Pages: 100330-100330
  • DOI: 10.1016/j.esmoop.2021.100330
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Prospect of lenvatinib for unresectable hepatocellular carcinoma in the new era of systemic chemotherapy (2021)
  • Author(s): Sho Takuya、Morikawa Kenichi、Kubo Akinori、Tokuchi Yoshimasa、Kitagataya Takashi、Yamada Ren、Shigesawa Taku、Kimura Mugumi、Nakai Masato、Suda Goki、Natsuizaka Mitsuteru、Ogawa Koji、Sakamoto Naoya
  • Journal Title: World Journal of Gastrointestinal Oncology Volume: 13 Issue: 12 Pages: 2076-2087
  • DOI: 10.4251/wjgo.v13.i12.2076
  • Peer Reviewed / Open Access
• [Journal Article] Tenofovir-disoproxil-fumarate modulates lipid metabolism via hepatic CD36/PPAR-alpha activation in hepatitis B virus infection (2021)
  • Author(s): Suzuki K, Suda G, Yamamoto Y, Furuya K, Baba M, Nakamura A, Miyoshi H, Kimura M, Maehara O, Yamada R, Kitagataya T, Yamamoto K, Shigesawa T, Nakamura A, Ohara M, Kawagishi N, Nakai M, Sho T, Natsuizaka M, Morikawa K, Ogawa K, Ohnishi S, Sakamoto N
  • Journal Title: J Gastroenterol. Volume: 56 Issue: 2 Pages: 168-180
  • DOI: 10.1007/s00535-020-01750-3
  • Peer Reviewed
• [Journal Article] Recent advances in the treatment of hepatitis C virus infection for special populations and remaining problems (2021)
  • Author(s): Suda G, Sakamoto N
  • Journal Title: J Gastroenterol Hepatol. Volume: in press Issue: 5 Pages: 1152-1158
  • DOI: 10.1111/jgh.15189
  • Peer Reviewed
• [Journal Article] Time-dependent changes in the seroprevalence of COVID-19 in asymptomatic liver disease outpatients in an area in Japan undergoing a second wave of COVID-19 (2020)
  • Author(s): Suda G, Ogawa K, Kimura M, Maehara O, Kitagataya T, Ohara M, Tokuchi Y, Kubo A, Yamada R, Shigesawa T, Suzuki K, Kawagishi N, Nakai M, Sho T, Natsuizaka M, Morikawa K, Sakamoto N.
  • Journal Title: Hepatol Res. Volume: 5- Issue: 10 Pages: 1196-1200
  • DOI: 10.1111/hepr.13551
  • Peer Reviewed
• [Journal Article] High serum angiopoietin‐2 level predicts non‐regression of liver stiffness measurement‐based liver fibrosis stage after direct‐acting antiviral therapy for hepatitis C (2020)
  • Author(s): Kawagishi Naoki、Suda Goki、Kimura Megumi、Maehara Osamu、Shimazaki Tomoe、Yamada Ren、Kitagataya Takashi、Shigesawa Taku、Suzuki Kazuharu、Nakamura Akihisa、Ohara Masatsugu、Umemura Machiko、Nakai Masato、Sho Takuya、Natsuizaka Mitsuteru、Morikawa Kenichi、Ogawa Koji、Kudo Yusuke、Nishida Mutsumi、Sakamoto Naoya
  • Journal Title: Hepatology Research Volume: in press Issue: 6 Pages: 671-681
  • DOI: 10.1111/hepr.13490
  • Peer Reviewed
• [Journal Article] Durable response without recurrence to Tolvaptan improves long-term survival (2020)
  • Author(s): Nakai M, Suda G, Kubo A, Tokuchi Y, Kitagataya T, Yamada R, Shigesawa T, Suzuki K, Nakamura A, Kawagishi N, Ohara M, Umemura M, Sho T, Morikawa K, Ogawa K, Sakamoto N.
  • Journal Title: J Gastroenterol. Volume: 55 Issue: 12 Pages: 1150-1161
  • DOI: 10.1007/s00535-020-01721-8
  • Peer Reviewed
• [Journal Article] Analysis of the optimal psoas muscle mass index cut-off values, as measured by computed tomography, for the diagnosis of loss of skeletal muscle mass in Japanese people. (2020)
  • Author(s): Ohara M, Suda G, Kimura M, Maehara O, Shimazaki T, Shigesawa T, Suzuki K, Nakamura A, Kawagishi N, Nakai M, Sho T, Natsuizaka M, Morikawa K, Ogawa K, Kobayashi T, Uebayashi M, Takagi R, Yokota I, Shimamura T, Sakamoto N.
  • Journal Title: Hepatol Res Volume: in press Issue: 6 Pages: 715-725
  • DOI: 10.1111/hepr.13499
  • Peer Reviewed
• [Journal Article] Prevalence, clinical course, and predictive factors of immune checkpoint inhibitor monotherapy-associated hepatitis in Japan. (2020)
  • Author(s): Kitagataya T, Suda G, Nagashima K, Katsurada T, Yamamoto K, Kimura M, Maehara O, Yamada R, Shigesawa T, Suzuki K, Nakamura A, Ohara M, Umemura M, Kawagishi N, Nakai M, Sho T, Natsuizaka M, Morikawa K, Ogawa K, Ohnishi S, Komatsu Y, Hata H, Takeuchi S, Abe T, Sakakibara-Konishi J, Teshima T, Homma A, Sakamoto N.
  • Journal Title: J Gastroenterol Hepatol Volume: in press Issue: 10 Pages: 1782-1788
  • DOI: 10.1111/jgh.15041
  • NAID: 120007160309
  • Peer Reviewed
• [Journal Article] Comparative Glycomic Analysis of Sialyl Linkage Isomers by Sialic Acid Linkage-Specific Alkylamidation in Combination with Stable Isotope Labeling of α2,3-Linked Sialic Acid Residues (2019)
  • Author(s): Hanamatsu Hisatoshi、Nishikaze Takashi、Tsumoto Hiroki、Ogawa Koji、Kobayashi Takashi、Yokota Ikuko、Morikawa Kenichi、Suda Goki、Sho Takuya、Nakai Masato、Miura Nobuaki、Higashino Kenichi、Sekiya Sadanori、Iwamoto Shinichi、Miura Yuri、Furukawa Jun-ichi、Tanaka Koichi、Sakamoto Naoya
  • Journal Title: Analytical Chemistry Volume: 91 Issue: 21 Pages: 13343-13348
  • DOI: 10.1021/acs.analchem.9b03617
  • Peer Reviewed
• [Journal Article] Effects of resistance-associated variants in genotype 2 hepatitis C virus on viral replication and susceptibility to antihepatitis C virus drugs. (2019)
  • Author(s): Suda G, Kimura M, Shigesawa T, Suzuki K, Nakamura A, Ohara M, Kawagishi N, Nakai M, Sho T, Maehara O, Shimazaki T, Morikawa K, Natsuizaka M, Ogawa K, Sakamoto N.
  • Journal Title: Hepatol Res Volume: 49 Issue: 11 Pages: 1275-1285
  • DOI: 10.1111/hepr.13401
  • Peer Reviewed