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Designing novel protease inhibitors based on the interference of mouse APOBEC3 with retroviral Gag-Pol autocatalysis

Research Project

Project/Area Number 16H05199
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Virology
Research InstitutionKindai University

Principal Investigator

MIYAZAWA Masaaki  近畿大学, 医学部, 教授 (60167757)

Co-Investigator(Kenkyū-buntansha) 博多 義之  近畿大学, 医学部, 講師 (30344500)
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥14,430,000 (Direct Cost: ¥11,100,000、Indirect Cost: ¥3,330,000)
Fiscal Year 2018: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2017: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2016: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Keywordsレトロウイルス / 宿主因子 / 複製阻害 / プロテアーゼ / APOBEC3 / 粒子成熟 / Gag-Pol前駆体 / 複製制限 / タンパク質相互作用 / プロセシング / HIV-1 / マウスレトロウイルス / ウイルス / タンパク質間相互作用 / ヒト免疫不全ウイルス / ウイルスプロテアーゼ / タンパク質プロセシング / 分子間相互作用
Outline of Final Research Achievements

Mouse APOBEC3 (mA3) inhibits murine leukemia virus (MuLV) replication through a deamination-independent mechanism in which the reverse transcription is considered the prime target process. However, other steps in virus replication can also be targeted by mA3. We have investigated the possible effect of mA3 on viral protease-mediated processes. We found that mA3 directly bound both mature viral protease and Pr180gag-pol precursor. Furthermore, the autoprocessing of Pr180gag-pol was impeded by mA3, resulting in reduced production of mature viral protease. Exon 5-containing and -lacking isoforms of mA3 equally exhibited this antiviral activity, and physiologically expressed levels of mA3 impeded Pr180gag-pol autocatalysis and Pr65gag processing. This blockade was independent of the deaminase activity and required the C-terminal half of mA3. These results suggest that Pr180gag-pol autoprocessing can be a critical step for mA3 to exert its deaminase-independent antiretroviral activity.

Academic Significance and Societal Importance of the Research Achievements

抗レトロウイルス薬の多剤併用により、先進国ではHIV-1感染者の生命予後が非感染者のそれに近付いているとされる。しかし、現在用いられている抗レトロウイルス薬では耐性株出現が不可避であり、若年感染者が短期間に治療を必要とするようになる現状からも、新たな作用機序を持つ抗HIV薬開発が喫緊の課題である。プロテアーゼ阻害薬は、活性部位への結合や二量体化の抑制を指標に開発されて来た。我々の研究成果を基礎に、Gag-Pol前駆体からのプロテアーゼ切り出しを阻害する薬物のシーズを宿主因子の分子構造から探ることにより、有効でかつ副作用の少ない新規抗レトロウイルス薬の開発に貢献できる可能性がある。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • Research Products

    (26 results)

All 2019 2018 2017 2016 Other

All Int'l Joint Research (1 results) Journal Article (7 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 6 results,  Open Access: 4 results,  Acknowledgement Compliant: 2 results) Presentation (14 results) (of which Int'l Joint Research: 8 results,  Invited: 4 results) Book (1 results) Remarks (2 results) Funded Workshop (1 results)

  • [Int'l Joint Research] National Institutes of Health(米国)

    • Related Report
      2017 Annual Research Report
  • [Journal Article] A leucine zipper-based peptide hybrid delivers functional Nanog protein inside the cell nucleus.2019

    • Author(s)
      Yoshiyuki Hakata, Hiroyuki Michiue, Takashi Ohtsuki, Masaaki Miyazawa and Mizuki Kitamatsu
    • Journal Title

      Bioorganic & Medicinal Chemistry Letters

      Volume: 29 Issue: 7 Pages: 878-881

    • DOI

      10.1016/j.bmcl.2019.02.004

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] フレンドウイルス感染マウスにおける白血病発症機構2019

    • Author(s)
      塚本 徹雄、河原佐智代、宮澤正顯
    • Journal Title

      Bio Clinica

      Volume: 印刷中

    • Related Report
      2018 Annual Research Report
  • [Journal Article] B7-H3 negatively modulates CTL-mediated cancer immunity2018

    • Author(s)
      Yonesaka K, Haratani K, Takamura S, Sakai H, Kato R, Takegawa N, Takahama T, Tanaka K, Hayashi H, Takeda M, Kato S, Maenishi O, Sakai K, Chiba Y, Okabe T, Kudo K, Hasegawa Y, Kaneda H, Yamato M, Hirotani K, Miyazawa M, Nishio K, Nakagawa K.
    • Journal Title

      Clin Cancer Res.

      Volume: - Issue: 11 Pages: 2653-2664

    • DOI

      10.1158/1078-0432.ccr-17-2852

    • Related Report
      2018 Annual Research Report 2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] SIV targeting of CXCR3+CD4+ T cells in secondary lymphoid organs associates with robust CXCL10 expression in monocyte/macrophage subsets.2017

    • Author(s)
      Fujino, M., H. Sato, T. Okamura, A. Uda, S. Takeda, N. Ahmed, S. Shichino, T. Shiino, Y. Saito, S. Watanabe, C. Sugimoto, M. Kuroda, M. Ato, Y. Nagai, S. Izumo, K. Matsushima, M. Miyazawa, A. Ansari, F. Villinger, and K. Mori
    • Journal Title

      Journal of Virology

      Volume: 印刷中 Issue: 13

    • DOI

      10.1128/jvi.00439-17

    • Related Report
      2017 Annual Research Report 2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Repression of miRNA function mediates inflammation-associated colon tumorigenesis.2017

    • Author(s)
      Yoshikawa T., J. F. Wu, M. Otsuka, T. Kishikawa, N. Suzuki, A. Takata, M. Ohno, R. Ishibashi, M. Yamagami, R. Nakagawa, N. Kato, M. Miyazawa, J. Han, and K. Koike
    • Journal Title

      Gastroenterology

      Volume: 152 Issue: 3 Pages: 631-643

    • DOI

      10.1053/j.gastro.2016.10.043

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Functional polymorphisms and molecular evolution of mouse APOBEC32016

    • Author(s)
      宮澤 正顯,博多 義之,武田 英里,李 君,河原 佐智代
    • Journal Title

      生化学

      Volume: 88 Issue: 5 Pages: 582-592

    • DOI

      10.14952/SEIKAGAKU.2016.880582

    • ISSN
      0037-1017
    • Year and Date
      2016-10-25
    • Related Report
      2016 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Specific niches for lung-resident memory CD8+ T cells at the site of tissue regeneration enable CD69-independent maintenance.2016

    • Author(s)
      Takamura, S., H. Yagi, Y. Hakata, C. Motozono, S. R. McMaster, T. Masumoto, M. Fujisawa, T. Chikaishi, J. Komeda, J. Itoh, M. Umemura, A. Kyusai, M. Tomura, T. Nakayama, D. L. Woodland, J. E. Kohlmeier, and M. Miyazawa
    • Journal Title

      The Journal of Experimental Medicine

      Volume: 213 Issue: 13 Pages: 3057-3073

    • DOI

      10.1084/jem.20160938

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Presentation] Mouse APOBEC3 interferes with proteolytic autoprocessing of Gag-Pol polyprotein and inhibits Gag processing.2018

    • Author(s)
      Yoshiyuki Hakata, Jun Li, Takahiro Fujino, Yuki Tanaka, Rie Shimizu, and Masaaki Miyazawa
    • Organizer
      The 30th International Workshop on Retroviral Pathogenesis
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] The requirement of B cell-intrinsic TLR7 for the production of retrovirus-neutralizing antibodies is overcome by T helper cells in an epitope-specific manner.2018

    • Author(s)
      Sachiyo Tsuji-Kawahara and Masaaki Miyazawa
    • Organizer
      The 30th International Workshop on Retroviral Pathogenesis
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Fate determination with a selected epitope facilitates follicular helper T cell differentiation and protection against acute retroviral infection.2018

    • Author(s)
      Shigeki Kato, Chihiro Motozono, Sachiyo Kawahara and Masaaki Miyazawa
    • Organizer
      The 30th International Workshop on Retroviral Pathogenesis
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Expression of galectin-9 in normal bone marrow and Friend virus-induced erythroleukemia cells.2018

    • Author(s)
      Tetsuo Tsukamoto and Masaaki Miyazawa
    • Organizer
      The 30th International Workshop on Retroviral Pathogenesis
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] エピトープ特異性によるCD4陽性エフェクターT細胞機能の制御と腫瘍免疫2018

    • Author(s)
      宮澤 正顯
    • Organizer
      第69回日本皮膚科学会中部支部学術大会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] Mouse APOBEC3 disrupts proteolytic autoprocessing of retroviral Gag-Pol precursors through direct binding to the protease domain2017

    • Author(s)
      Masaaki Miyazawa, Yoshiyuki Hakata, Jun Li, Takahiro Fujino, and Yuki Tanaka
    • Organizer
      The 29th International Workshop on Retroviral Pathogenesis
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] A Checkpoint Molecule B7-H3 as a Novel Immune Therapy Target for Non-Small Cell Lung Cancer (NSCLC)2017

    • Author(s)
      K. Yonesaka, K. Kudoh, S. Takamura, H. Sakai, R. Kato, K. Haratani, T. Takahama, K. Tanaka, H. Hayashi, H. Kaneda, M. Takeda, O. Maenishi, M. Yamato, M. Miyazawa, K. Nishio, K. Nakagawa
    • Organizer
      18th World Conference on Lung Cancer
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] T細胞受容体親和性による感染防御性CD4陽性T細胞分化の制御2017

    • Author(s)
      宮澤 正顯
    • Organizer
      第26回日本組織適合性学会大会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] T-helper cell fate determination and Toll-like receptor 7 overriding by priming with a selected retroviral epitope.2016

    • Author(s)
      Miyazawa, M., Motozono, C., Tsuji-Kawahara, S., and Kato, S.
    • Organizer
      The 28th International Workshop on Retroviral Pathogenesis
    • Place of Presentation
      Bourbon Orleans Hotel, New Orleans, Louisiana, U.S.A.
    • Year and Date
      2016-12-05
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Vaccine-elicited preferential induction of germinal center follicular helper T cells is associated with protection against retroviral infection.2016

    • Author(s)
      Motozono, C., Tsuji-Kawahara, S., Takamura, S., Yagi, H., Miyazawa, M.
    • Organizer
      The 44th Annual Meeting of the Japanese Society for Immunology
    • Place of Presentation
      Sapporo Convention Center, Sapporo
    • Year and Date
      2016-11-18
    • Related Report
      2016 Annual Research Report
  • [Presentation] Autophagy-independent maintenance of resident memory CD8+ T cells in the lung.2016

    • Author(s)
      Takamura S. and Miyazawa, M.
    • Organizer
      The 44th Annual Meeting of the Japanese Society for Immunology
    • Place of Presentation
      Sapporo Convention Center, Sapporo
    • Year and Date
      2016-11-18
    • Related Report
      2016 Annual Research Report
  • [Presentation] B cell-intrinsic TLR7 signaling is required to prevent the generation of recombinant viruses follwoing retrovirus infection.2016

    • Author(s)
      Tsuji-Kawahara, S., Kawasaki, Y., Motozono, C., Takamura, S., and Miyazawa, M.
    • Organizer
      The 44th Annual Meeting of the Japanese Society for Immunology
    • Place of Presentation
      Sapporo Convention Center, Sapporo
    • Year and Date
      2016-11-18
    • Related Report
      2016 Annual Research Report
  • [Presentation] Functional evolution of retrovirus restriction enzyme APOBEC3: Genetic polymorphisms and isoforms.2016

    • Author(s)
      Miyazawa, M.
    • Organizer
      The 2nd International Symposium on Molecular Basis of Virus-Host Interactions
    • Place of Presentation
      ACU and Sapporo Convention Center, Sapporo
    • Year and Date
      2016-10-22
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] CD4陽性T細胞認識エピトープが決める感染防御免疫応答の行方2016

    • Author(s)
      宮澤正顯
    • Organizer
      2016年度眼科COI学術講演会
    • Place of Presentation
      ヒルトン大阪, 大阪市
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Book] 解明病理学第3版2017

    • Author(s)
      青笹克之、加藤光保、菅野 祐幸編 宮澤 正顯 章分担
    • Total Pages
      818
    • Publisher
      医歯薬出版
    • ISBN
      9784263731789
    • Related Report
      2017 Annual Research Report
  • [Remarks] 近畿大学医学部免疫学教室

    • URL

      https://www.med.kindai.ac.jp/immuno/

    • Related Report
      2018 Annual Research Report
  • [Remarks] 近畿大学医学部免疫学教室

    • URL

      http://www.med.kindai.ac.jp/immuno/

    • Related Report
      2017 Annual Research Report 2016 Annual Research Report
  • [Funded Workshop] The 30th International Workshop on Retroviral Pathogenesis2018

    • Related Report
      2018 Annual Research Report

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Published: 2016-04-21   Modified: 2022-05-20  

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