Development of novel antiviral therapy targeting hepatitis B virus host restriction factor

• Project/Area Number: 20K08371
• 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: Morikawa Kenichi 北海道大学, 医学研究院, 客員研究員 (60384377)
• Co-Investigator(Kenkyū-buntansha): 坂本 直哉 北海道大学, 医学研究院, 教授 (10334418) ; 須田 剛生 北海道大学, 大学病院, 特任助教 (20447460) ; 武井 則雄 北海道大学, 医学研究院, 助教 (50523461)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: HBV / 宿主因子 / HBx / 宿主制限因子 / B型肝炎ウイルス / HBs抗原 / HBc抗原 / HBx蛋白

Outline of Research at the Start

本研究は抗HBV宿主制限因子の新規同定および解明されていない機序の基礎的研究に取り組むことにより、HBV cccDNAの排除を含んだ”完全”治癒を目指した新規治療法の開発研究を行う。研究期間内には以下のことを明らかにする。
1) HBs抗原に関与する宿主因子の探索
2) HBc抗原に関与する宿主因子の探索
3) HBx抗原に関与する宿主因子の探索
4) 抗HBV宿主制限因子を増強する新規化合物の探索
本研究により、将来的に抗HBV宿主制限因子をターゲットにした新規治療法の開発と、HBV再活性化予防への貢献、肝臓癌発生・進展および再発阻止に寄与する癌予防医学への貢献が期待される。

Outline of Final Research Achievements

The aim of this study was to identify and analyze the function of host restriction factors with anti-HBV activity targeting HBV cccDNA. We established a cell line derived from U2-OS cells that can regulate expression of a Myc-tagged protein on HBx in a drug-inducible manner. Proteome analysis of these cells identified SMC5/6, a host restriction factor for HBV, and immuno-precipitation experiments using DDB1 subunits and HBx to recover SMC5/6 by inhibiting HBx binding to DDB1 confirmed the presence of a novel HBx binding region in DDB1. We confirmed the existence of a new HBx binding region in DDB1, which is different from the known region. We also confirmed the inhibition of HBx-DDB1 binding using synthetic peptides bearing the novel binding site.

Academic Significance and Societal Importance of the Research Achievements

B型肝炎ウイルス（hepatitis B virus: HBV）感染肝細胞核内には、完全閉鎖型二本鎖DNA（covalently closed circular DNA: cccDNA）が形成される。慢性B型肝炎・肝硬変にはインターフェロンおよび核酸アナログ製剤が使用され一定の効果を上げているが、いずれもcccDNAには影響せず、免疫抑制療法および化学療法でのHBV再活性化や発がんのリスクは残存したままとなっている。
本研究により、将来的に抗HBV宿主制限因子をターゲットにした新規治療法の開発と、HBV再活性化予防への貢献、肝臓癌発生・進展および再発阻止に寄与する癌予防医学への貢献が期待される。

Research Products

• [Journal Article] Prophylactic tenofovir alafenamide for hepatitis B virus reactivation and reactivation‐related hepatitis (2023)
  • Author(s): Suda Goki、et al.,
  • Journal Title: Journal of Medical Virology Volume: 95 Issue: 2
  • DOI: 10.1002/jmv.28452
  • Peer Reviewed
• [Journal Article] Serum IL-1β predicts de novo hepatitis B virus reactivation during direct-acting antiviral therapy for hepatitis C, not during anti-cancer/immunosuppressive therapy (2022)
  • Author(s): Kawagishi Naoki、Suda Goki et al.,
  • Journal Title: Scientific Reports Volume: 12 Issue: 1
  • DOI: 10.1038/s41598-022-21315-z
  • Peer Reviewed / Open Access
• [Journal Article] Pre-sarcopenia and Mac-2 binding protein glycosylation isomer as predictors of recurrence and prognosis of early-stage hepatocellular carcinoma (2022)
  • Author(s): Nakai Masato、Morikawa Kenichi、et al.
  • Journal Title: World Journal of Hepatology Volume: 14 Issue: 7 Pages: 1480-1494
  • DOI: 10.4254/wjh.v14.i7.1480
  • Peer Reviewed / Open Access
• [Journal Article] Incidence of post‐transplant hepatitis B virus reactivation with the use of kidneys from donors with resolved hepatitis B virus infection (2022)
  • Author(s): Yamada Ren、Morikawa Kenichi、et al.
  • Journal Title: Journal of Viral Hepatitis Volume: 29 Issue: 11 Pages: 976-985
  • DOI: 10.1111/jvh.13740
  • Peer Reviewed
• [Journal Article] Efficacy of rifaximin against covert hepatic encephalopathy and hyperammonemia in Japanese patients (2022)
  • Author(s): Nakai Masato、Morikawa Kenichi、et al.
  • Journal Title: PLOS ONE Volume: 17 Issue: 7 Pages: e0270786-e0270786
  • DOI: 10.1371/journal.pone.0270786
  • 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] Effects of nucleos(t)ide analogs on hepatitis B surface antigen reduction with interferon-lambda 3 induction in chronic hepatitis B patients (2022)
  • Author(s): Umemura M, Ogawa K, Morikawa K, Kubo A, Tokuchi Y, Yamada R, Kitagataya T, Shigesawa T, Shimazaki T, Kimura M, Suzuki K, Nakamura A, Ohara M, Kawagishi N, Izumi T, Nakai M, Sho T, Suda G, Natsuizaka M, Ono K, Murata K, Sugiyama M, Mizokami M, Sakamoto N
  • Journal Title: Hepatol Res Volume: 52 Issue: 7 Pages: 586-596
  • DOI: 10.1111/hepr.13768
  • Peer Reviewed
• [Journal Article] The potential of soluble CD14 in discriminating nonalcoholic steatohepatitis from nonalcoholic fatty liver disease (2022)
  • Author(s): Nakamura Akihisa、Yamamoto Koji、Sakamoto Naoya et al.
  • Journal Title: Hepatology Research Volume: - Issue: 6 Pages: 508-521
  • DOI: 10.1111/hepr.13757
  • 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] 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] 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] 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] 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] 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] 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] 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] 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] 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] 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] 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] 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] Baseline angiopoietin‐2 and FGF19 levels predict treatment response in patients receiving multikinase inhibitors for hepatocellular carcinoma (2020)
  • Author(s): Shigesawa Taku、Suda Goki、Kimura Megumi、Shimazaki Tomoe、Maehara Osamu、Yamada Ren、Kitagataya Takashi、Suzuki Kazuharu、Nakamura Akihisa、Ohara Masatsugu、Umemura Machiko、Kawagishi Naoki、Nakai Masato、Sho Takuya、Natsuizaka Mitsuteru、Morikawa Kenichi、Ogawa Koji、Sakamoto Naoya
  • Journal Title: JGH Open Volume: 4 Issue: 5 Pages: 880-888
  • DOI: 10.1002/jgh3.12339
  • Peer Reviewed / Open Access
• [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] OCIAD1 is a host mitochondrial substrate of the hepatitis C virus NS3-4A protease (2020)
  • Author(s): Tran Huong T. L.、Morikawa Kenichi、Anggakusuma、Zibi Rose、Thi Viet Loan Dao、Penin Fran?ois、Heim Markus H.、Quadroni Manfredo、Pietschmann Thomas、Gouttenoire J?r?me、Moradpour Darius
  • Journal Title: PLOS ONE Volume: 15 Issue: 7 Pages: 236447-236447
  • DOI: 10.1371/journal.pone.0236447
  • Peer Reviewed / Open Access
• [Journal Article] Lenvatinib in patients with unresectable hepatocellular carcinoma who do not meet the REFLECT trial eligibility criteria (2020)
  • Author(s): Sho Takuya、Morikawa Kenichi et al.
  • Journal Title: Hepatology Research Volume: 50 Issue: 8 Pages: 966-977
  • DOI: 10.1111/hepr.13511
  • Peer Reviewed
• [Journal Article] Lenvatinib suppresses cancer stem-like cells in HCC by inhibiting FGFR1-3 signaling, but not FGFR4 signaling (2020)
  • Author(s): Shigesawa Taku、Morikawa Kenichi et al.
  • Journal Title: Carcinogenesis Volume: 42 Issue: 1 Pages: 58-69
  • DOI: 10.1093/carcin/bgaa049
  • Peer Reviewed / Open Access
• [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
• [Presentation] 肝癌に対する新世代マイクロ波凝固療法の治療成績 (2022)
  • Author(s): 中井正人, 吉田苑永, 細田峻一, 久保彰則, 得地祐匡, 北潟谷隆, 山田 錬, 重沢 拓,荘 拓也, 須田剛生, 森川賢一, 小川浩司, 坂本直哉.
  • Organizer: 第130回日本消化器病学会北海道地方会
• [Presentation] 再活性化が疑われた急性E型肝炎の1例 (2022)
  • Author(s): 久保彰則, 小川浩司, 吉田苑永, 細田峻一, 得地祐匡, 北潟谷隆, 山田 錬, 重沢 拓, 中井正人, 荘 拓也, 須田剛生, 森川賢一, 石田勢津子, 坂本直哉
  • Organizer: 第130回日本消化器病学会北海道地方会
• [Presentation] Lenvatinib加療後にCRに至りconversion surgeryを施行した肝内多発転移を伴う肝細胞癌の1例 (2021)
  • Author(s): 細田峻一, 中井正人, 吉田苑永, 久保彰則, 得地祐匡, 北潟谷隆, 山田 錬, 荘 拓也, 須田剛生, 森川賢一, 小川浩司, 坂本直哉, 岡崎ななせ, 大塚拓也, 三橋智子
  • Organizer: 第129回日本消化器病学会北海道地方会
• [Presentation] 当院における切除不能肝細胞癌に対するアテゾリズマブ＋ベバシズマブ療法の使用経験 (2021)
  • Author(s): 吉田苑永, 荘 拓也, 久保彰則, 得地祐匡, 細田峻一, 北潟谷隆, 山田 錬, 中井正人,須田剛生, 森川賢一, 小川浩司, 坂本直哉
  • Organizer: 第129回日本消化器病学会北海道地方会
• [Presentation] 肝疾患患者における筋肉量の経時変化の評価はBIA法に比べCT画像を用いた方法が有用である (2021)
  • Author(s): 大原正嗣, 須田剛生, 重沢 拓, 鈴木和治, 中村晃久, 川岸直樹, 中井正人, 荘 拓也,小川浩司, 森川賢一, 坂本直哉
  • Organizer: 第57回日本肝臓学会総会
• [Presentation] 部分的脾動脈塞栓術(PSE), バルーン閉塞下逆行性経静脈的塞栓術(BRTO)の肝予備能, 線維化マーカー, 予後への影響 (2021)
  • Author(s): 5.中井正人, 小川浩司, 坂本直哉, 久保彰則, 得地祐匡, 北潟谷隆, 山田 錬, 重沢 拓, 荘 拓也, 須田剛生, 森川賢一
  • Organizer: 第57回日本肝臓学会総会
• [Presentation] 腸内細菌叢を標的としたNASH治療戦略の検討 (2021)
  • Author(s): 山田 錬, 森川賢一, 坂本直哉
  • Organizer: 第57回日本肝臓学会総会
• [Presentation] フォンタン術後肝合併症の現状と5年経過からみえてくること (2021)
  • Author(s): 荘 拓也, 森川賢一, 坂本直哉
  • Organizer: 第57回日本肝臓学会総会
• [Presentation] 肝炎ウイルス複製・病原性と関連する宿主因子のプロテオーム解析 (2021)
  • Author(s): 森川賢一, 久保彰則, 坂本直哉
  • Organizer: 第57回日本肝臓学会総会
• [Presentation] B型肝炎ウイルス宿主制限因子の回復を目指した創薬研究 (2021)
  • Author(s): 森川賢一, 山田 錬, 坂本直哉
  • Organizer: 第57回日本肝臓学会総会
• [Presentation] 脂質異常症を合併する非アルコール性脂肪性肝疾患患者に対するペマフィブラート投与効果の検討 (2021)
  • Author(s): 久保彰則, 森川賢一, 坂本直哉
  • Organizer: 第57回日本肝臓学会総会
• [Presentation] シンポジウム4 肝疾患と微小環境 総括 (2020)
  • Author(s): 森川賢一
  • Organizer: 第56回日本肝臓学会総会
  • Invited
• [Presentation] ストレス応答よりみえてくるB型およびC型肝炎ウイルスの戦略 (2020)
  • Author(s): 森川賢一, 須田剛生, 坂本直哉.
  • Organizer: 第56回日本肝臓学会総会
• [Book] 今日の診断指針-第8版-. ウイルス性肝炎. (2020)
  • Author(s): 森川賢一
  • Total Pages: 2115
  • Publisher: (株)医学書院
• [Book] 今日の治療指針-私はこう治療している-2020年度版. 肝疾患患者の生活指導. (2020)
  • Author(s): 森川賢一
  • Total Pages: 2079
  • Publisher: (株)医学書院
• [Remarks] 北海道大学大学院医学研究院内科学講座消化器内科学教室
  • URL: https://halo.med.hokudai.ac.jp/
• [Remarks] 北海道大学大学院医学研究院消化器内科学教室
  • URL: http://halo.med.hokudai.ac.jp/
• [Remarks] 北海道大学大学院医学研究院消化器内科学教室ホームページ
  • URL: http://halo.med.hokudai.ac.jp/
• [Remarks] 北海道大学研究者総覧
  • URL: https://researchers.general.hokudai.ac.jp/profile/ja.153bd8513bc85e0c520e17560c007669.html