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

• Project/Area Number: 24591485
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Infectious disease medicine
• Research Institution: National 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: ¥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)
• Keywords: HIV-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.

Research Products

• [Journal Article] Passive transfer of neutralizing monoclonal antibody KD-247 reduces 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 Pages: 453-462
  • DOI: 10.1097/qad.0000000000000570
  • 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
  • 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 Pages: 1-11
  • DOI: 10.1096/fj.14-252262
  • 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: J. Gen. Virol. Volume: 95 Pages: 1816-1826
  • DOI: 10.1099/vir.0.062885-0
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Impact of antiretroviral pressure on selection of primary HIV-1 envelope sequences in vitro. (2013)
  • Author(s): Shigeyoshi Harada, Kazuhisa Yoshimura, Aki Yamaguchi, Samatchaya Boonchawalit, Keisuke Yusa, Shuzo Matsushita.
  • Journal Title: J. Gen. Virol. Volume: 94 Pages: 933-943
  • DOI: 10.1099/vir.0.047167-0
  • 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: Journal of Virology Volume: in press Pages: 5424-5436
  • DOI: 10.1128/jvi.00201-13
  • 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: Bioorgan & Medical Chemistry Volume: 8 Pages: 2518-2526
  • DOI: 10.1016/j.bmc.2013.02.041
  • 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 Volume: 4 Pages: 1-7
  • DOI: 10.3389/fmicb.2013.00117
  • Peer Reviewed
• [Journal Article] A CD4 mimic as an HIV entry inhibitor: Pharmacokinetics. (2013)
  • 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: Bioorgan & Medical Chemistry Volume: 21 Pages: 7884-7889
  • DOI: 10.1016/j.bmc.2013.10.005
  • Peer Reviewed
• [Journal Article] Generation of a Replication-competent Simian–human 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: Journal of General Virology Volume: 94 Pages: 2710-2716
  • DOI: 10.1099/vir.0.055590-0
  • 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
  • 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
  • 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
• [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
  • 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
• [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
• [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)
• [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)
• [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)
• [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)
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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