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Development of novel entry inhibitors with inducing conformational change of Non-B HIV-1 envelope.

Research Project

Project/Area Number 24591485
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Infectious disease medicine
Research InstitutionNational Institute of Infectious Diseases

Principal Investigator

YOSHIMURA Kazuhisa  国立感染症研究所, その他部局等, その他 (60315306)

Project Period (FY) 2012-04-01 – 2015-03-31
Project Status Completed (Fiscal Year 2014)
Budget Amount *help
¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
KeywordsHIV-1 / entry inhibitors / Betulinic acid / envelope / CD4 mimic / 侵入阻害剤 / subtype non-B / gp120 / Envelope / NBD誘導体 / 中和抗体
Outline of Final Research Achievements

We found many novel entry inhibitors (Betulinic acid analogues) that could inhibit infection of HIV-1. We also found that combinations of the Betulinic acid analogues with anti-gp120 MAbs showed synergistic interactions against HIV-1 not only subtype B but also subtype non-B. These findings suggest that small compounds such as Betulinic acid analogues may enhance the neutralizing activities of CD4i and anti-V3 Abs in vivo.

Report

(4 results)
  • 2014 Annual Research Report   Final Research Report ( PDF )
  • 2013 Research-status Report
  • 2012 Research-status Report
  • Research Products

    (32 results)

All 2015 2014 2013 2012

All Journal Article (12 results) (of which Peer Reviewed: 12 results,  Open Access: 2 results,  Acknowledgement Compliant: 2 results) Presentation (20 results) (of which Invited: 1 results)

  • [Journal Article] Passive transfer of neutralizing monoclonal antibody KD-247reduces plasma viral load in patients chronically infected with HIV-1.2015

    • Author(s)
      Matsushita, S., Yoshimura, K., Ramirez, K.P., Pisupati, J., Murakami, T.
    • Journal Title

      AIDS

      Volume: 29 Issue: 4 Pages: 453-462

    • DOI

      10.1097/qad.0000000000000570

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Complementary and synergistic activities of anti-V3, CD4bs and CD4i antibodies derived from a single individual can cover a wide range of HIV-1 strains.2015

    • Author(s)
      Ramirez, K.P., Kuwata, T., Maruta, Y, Tanaka K., Muntasir, A., Yoshimura, K., Matsushita, S.
    • Journal Title

      Virology

      Volume: 475 Pages: 187-203

    • DOI

      10.1016/j.virol.2014.11.011

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Structural basis of clade-specific HIV-1 neutralization by humanized anti-V3 monoclonal antibody KD-247.2015

    • Author(s)
      Kirby, K.A., Ong Y.T., Hachiya, A., Laughlin, T.G.,Chiang, L.A., Pan Y., Moran, J.L., Marchand, B.,Singh, K., Gallazzi, F., Quinn, T.P., Yoshimura, K., Murakami, T., Matsushita S., Sarafianos, S.G.
    • Journal Title

      The FASEB Journal

      Volume: 29 Issue: 1 Pages: 1-11

    • DOI

      10.1096/fj.14-252262

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Impact of maraviroc-resistant and low-CCR5- adapted mutations induced by in vitro passage on sensitivity to anti-envelope neutralizing antibodies.2014

    • Author(s)
      Kazuhisa Yoshimura, Shigeyoshi Harada, Samatchaya Boonchawalit, Yoko Kawanami, Shuzo Matsushita.
    • Journal Title

      Journal of General Virology

      Volume: 95 Issue: 8 Pages: 1816-1826

    • DOI

      10.1099/vir.0.062885-0

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Impact of antiretroviral pressure on selection of primary human immunodeficiency virus type 1 envelope sequences in vitro.2013

    • Author(s)
      Shigeyoshi Harada, Kazuhisa Yoshimura, Aki Yamaguchi, Samatchaya Boonchawalit, Keisuke Yusa, Shuzo Matsushita.
    • Journal Title

      Journal of General Virology

      Volume: 94 Issue: 5 Pages: 933-943

    • DOI

      10.1099/vir.0.047167-0

    • Related Report
      2013 Research-status Report 2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Conformational epitope consisting of the V3 and V4 loops as a target for potent and broad neutralization of simian immunodeficiency viruses.2013

    • Author(s)
      Kuwata T
    • Journal Title

      J Virol.

      Volume: in press Issue: 10 Pages: 933-943

    • DOI

      10.1128/jvi.00201-13

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] CD4 Mimics as HIV Entry Inhibitors: Lead Optimization Studies of the Aromatic Substituents.2013

    • Author(s)
      Narumi, T., Arai, H., Yoshimura, K., Harada, S., Hirota, Y., Ohashi, N., Hashimoto, C.. Nomura, W., Matsushita, S. and Tamamura, H.
    • Journal Title

      Bioorg. Med. Chem.

      Volume: 8 Issue: 9 Pages: 2518-2526

    • DOI

      10.1016/j.bmc.2013.02.041

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Increased infectivity in human cells and resistance to antibody-mediated neutralization by truncation of the SIV gp41 cytoplasmic tail.2013

    • Author(s)
      8. Kuwata, T.
    • Journal Title

      Frontiers in Microbiology/Virology.

      Volume: 4 Pages: 1-7

    • DOI

      10.3389/fmicb.2013.00117

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] A CD4 Mimic as an HIV Entry Inhibitors: Pharmacokinetics2013

    • Author(s)
      Hashimoto, C., Narumi, T., Otsuki, H., Hirota, Y., Arai, H., Yoshimura, K., Harada, S., Ohashi, N., Nomura, W., Miura, T., Igarashi, T., Matsuhita, S., Tamamura, H.
    • Journal Title

      Bioorg. Med. Chem.

      Volume: 21 Issue: 24 Pages: 7884-7889

    • DOI

      10.1016/j.bmc.2013.10.005

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Generation of a replication-competent simianhuman immunodeficiency virus, the neutralisation sensitivity of which can be enhanced in the presence of a small molecule CD4 mimic.2013

    • Author(s)
      Otsuki, H., Hishiki, T., Miura, T., Hashimoto, C., Narumi, T., Tamamura, H., Yoshimura, K., Matsushita, S., and Igarashi, T.
    • Journal Title

      J. Gen. Virol.

      Volume: 94 Issue: 12 Pages: 2710-2716

    • DOI

      10.1099/vir.0.055590-0

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Preparation of biologically active single-chain variable antibody fragments that target the HIV-1 gp120 V3 loop.2012

    • Author(s)
      Ong YT, Kirby KA, Hachiya A, Chiang LA, Marchand B, Yoshimura K, Murakami T, Singh K, Matsushita S, Sarafianos SG
    • Journal Title

      Cellular and Molecular Biology

      Volume: 58 Pages: 71-79

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Structural Dynamics of HIV-1 Envelope Gp120 Outer Domain with V3 Loop.2012

    • Author(s)
      Yokoyama M, Naganawa S, Yoshimura K, Matsushita S, Sato H
    • Journal Title

      PLoS ONE

      Volume: 7

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Presentation] Mutations at the bottom of the Phe43 cavity are responsible for cross-resistance to NBD analogues.2015

    • Author(s)
      Shigeyoshi Harada, Yu Irahara, Samatchaya Boonchawalit, Mai Goryo, Hirokazu Tamamura, Tetsuro Matano, Shuzo Matsushita, Kazuhisa Yoshimura.
    • Organizer
      The annual Conference on Retroviruses and Opportunistic Infections (CROI) 2015
    • Place of Presentation
      Seattle (USA)
    • Year and Date
      2015-02-23 – 2015-02-26
    • Related Report
      2014 Annual Research Report
  • [Presentation] Impact of the Drug-Escaped HIV Envelope Mutations on Susceptibility to Neutralizing Antibodies.2015

    • Author(s)
      Kazuhisa Yoshimura.
    • Organizer
      17th International Conference on Emerging Infectious Diseases (EID), AIDS Panel Meeting
    • Place of Presentation
      Taipei (Taiwan)
    • Year and Date
      2015-01-28 – 2015-01-29
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] Resistance Profile of CD4 Mimic Small Compounds (CD4MCs) and the Structure Analysis by Molecular Dynamic (MD) Simulation.2014

    • Author(s)
      Shigeyoshi Harada, Masaru Yokoyama, Samatchaya Boonchawalit, Hironori Sato, Shuzo Matsushita, Kazuhisa Yoshimura.
    • Organizer
      HIV Research For Prevention (HIVR4P) 2014
    • Place of Presentation
      Cape Town (South Africa)
    • Year and Date
      2014-10-28 – 2014-10-31
    • Related Report
      2014 Annual Research Report
  • [Presentation] Impact of Maraviroc (MVC)-resistant mutations in C1 and C4 regions of gp120 on sensitivity to antibody-mediated neutralization.2014

    • Author(s)
      Samatchaya Boonchawalit, Shigeyoshi Harada, Shuzo Matsushita, Kazuhisa Yoshimura.
    • Organizer
      20th International AIDS Conference
    • Place of Presentation
      Melbourne (Australia)
    • Year and Date
      2014-07-20 – 2014-07-25
    • Related Report
      2014 Annual Research Report
  • [Presentation] Impact of CD4 mimetics-resistant mutations on susceptibilities to anti-Env nMAbs.2014

    • Author(s)
      Shigeyoshi Harada, Samatchaya Boonchawalit, Tetsuo Narumi, Hirokazu Tamamura, Shuzo Matsushita, Kazuhisa Yoshimura
    • Organizer
      21th Conference on Retroviruses and Opportunistic Infections (CROI2014)
    • Place of Presentation
      Boston (USA)
    • Related Report
      2013 Research-status Report
  • [Presentation] In vitro selection of bifunctional CD4 mimic small compounds (NBD analogues) using bulk and cloned primary isolates.2013

    • Author(s)
      21th Conference on Retroviruses and Opportunistic Infections (CROI2014)
    • Organizer
      14th Kumamoto AIDS Seminar
    • Place of Presentation
      Kumamoto (Japan)
    • Related Report
      2013 Research-status Report
  • [Presentation] Indole-type small CD4 mimic molecules targeting an HIV envelope protein gp120.2013

    • Author(s)
      Yuki Hirota, Tetsuo Narumi, Kazuhisa Yoshimura, Shigeyoshi Harada, Chie Hashimoto, Wataru Nomura, Tatsuhiko Igarashi, Shuzo Matsushita, Hirokazu Tamamura
    • Organizer
      14th Kumamoto AIDS Seminar
    • Place of Presentation
      Kumamoto (Japan)
    • Related Report
      2013 Research-status Report
  • [Presentation] Analysis of interaction between gp120 and CD4 mimic small compounds that enhance the activity of anti-HIV neutralizing antibodies.2013

    • Author(s)
      Shigeyoshi Harada, Samatchaya Boonchawalit, Shuzo Matsushita, Kazuhisa Yoshimura
    • Organizer
      AIDS Vaccine 2013
    • Place of Presentation
      Barcelona (Spain)
    • Related Report
      2013 Research-status Report
  • [Presentation] バルクおよびクローンウイルスを用いたCD4類似低分子化合物誘導体に対するin vitro 耐性ウイルス誘導2013

    • Author(s)
      原田恵嘉, 鳴海哲夫, Samatchaya Boonchawalit, 玉村啓和, 松下修三, 吉村和久
    • Organizer
      第27回 日本エイズ学会学術集会・総会
    • Place of Presentation
      熊本
    • Related Report
      2013 Research-status Report
  • [Presentation] 抗V3抗体および低分子CD4ミミック曝露後投与によるアカゲザルでのSHIV複製抑制2013

    • Author(s)
      大附寛幸,丸田泰広,橋本智恵,鳴海哲夫,廣田雄樹, 原田恵嘉, 三浦智行, 吉村和久,玉村啓和,松下修三, 五十嵐樹彦
    • Organizer
      第27回 日本エイズ学会学術集会・総会
    • Place of Presentation
      熊本
    • Related Report
      2013 Research-status Report
  • [Presentation] In vitro selection of bifunctional CD4 mimic small compounds (NBD analogues) using bulk and cloned primary isolates.2013

    • Author(s)
      原田恵嘉, Samatchaya Boonchawalit, 松下修三, 吉村和久
    • Organizer
      第15回 白馬シンポジウム
    • Place of Presentation
      名古屋
    • Related Report
      2013 Research-status Report
  • [Presentation] Impact of Maraviroc-resistant and low CCR5-adapted mutations induced in vitro passage on sensitivity to anti-Env neutralizing antibodies.2013

    • Author(s)
      Yoshimura K, Harada S, Boonchawalit S, and Matsushita S
    • Organizer
      20th Conference on Retroviruses and Opportunistic Infections (CROI 2013)
    • Place of Presentation
      Atlanta, USA
    • Related Report
      2012 Research-status Report
  • [Presentation] CD4 mimic small compounds, NBD-556 and its analogues bind at three amino acid positions in the gp120 CD4 cavity.2013

    • Author(s)
      Harada S, Boonchawalit S, Narumi T, Tamamura H, Matsushita S, Yoshimura K
    • Organizer
      20th Conference on Retroviruses and Opportunistic Infections (CROI 2013)
    • Place of Presentation
      Atlanta, USA
    • Related Report
      2012 Research-status Report
  • [Presentation] In vitro induction of twelve CD4 mimic small compounds, NBD-556 and its analogues, resistant variants using primary R5 HIV-1.2012

    • Author(s)
      Harada S, Boonchawalit S, Narumi T, Tamamura H, Matsushita S, Yoshimura K
    • Organizer
      13th Kumamoto AIDS Seminar GCOE Joint International Symposium,
    • Place of Presentation
      Kumamoto, Japan
    • Related Report
      2012 Research-status Report
  • [Presentation] In vitro induction of ten CD4 mimic small compounds, NBD-556 and its analogues, resistant variants using primary R5 HIV-1.2012

    • Author(s)
      Harada S, Arai H, Narumi T, Tamamura H, Matsushita S, Yoshimura K
    • Organizer
      19th International AIDS Conference
    • Place of Presentation
      Washington DC, USA
    • Related Report
      2012 Research-status Report
  • [Presentation] R5臨床分離株を用いたCD4類似低分子化合物誘導体に対するin vitro耐性ウイルス誘導2012

    • Author(s)
      原田 恵嘉、鳴海 哲夫、玉村 啓和、松下 修三、吉村 和久
    • Organizer
      第26回日本エイズ学会学術集会・総会
    • Place of Presentation
      神奈川
    • Related Report
      2012 Research-status Report
  • [Presentation] SIV感染サルから分離された中和抗体B404はV3,V4ループを含むEnv立体構造を認識する2012

    • Author(s)
      桑田 岳夫、吉村 和久、松下 修三
    • Organizer
      第26回日本エイズ学会学術集会・総会
    • Place of Presentation
      神奈川
    • Related Report
      2012 Research-status Report
  • [Presentation] HIV外被タンパク質gp120を標的とするインドール型低分子CD4ミミックの創製研究2012

    • Author(s)
      廣田 雄樹、鳴海 哲夫、橋本 智恵、吉村 和久、原田 恵嘉、大附 寛幸、三浦 智行、五十嵐 樹彦、相川 春夫、野村 渉、松下 修三、玉村 啓和
    • Organizer
      第26回日本エイズ学会学術集会・総会
    • Place of Presentation
      神奈川
    • Related Report
      2012 Research-status Report
  • [Presentation] R5臨床分離株を用いた10種のCD4類似低分子化合物に対するin vitro 耐性ウイルス誘導2012

    • Author(s)
      原田 恵嘉、新井 啓之、鳴海 哲夫、玉村 啓和、松下 修三、吉村 和久
    • Organizer
      第14回白馬シンポジウム
    • Place of Presentation
      京都
    • Related Report
      2012 Research-status Report
  • [Presentation] CCR5阻害剤による耐性変異と中和抗体感受性2012

    • Author(s)
      吉村 和久
    • Organizer
      第14回白馬シンポジウム
    • Place of Presentation
      京都
    • Related Report
      2012 Research-status Report

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Published: 2013-05-31   Modified: 2019-07-29  

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