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Hybrids of Small-Molecule CD4 Mimics with Polyethylene Glycol Units as HIV Entry Inhibitors

  • Takuya Kobayakawa
    Takuya Kobayakawa
    Department of Medicinal Chemistry, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo 101-0062, Japan
  • Kohei Tsuji
    Kohei Tsuji
    Department of Medicinal Chemistry, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo 101-0062, Japan
    More by Kohei Tsuji
  • Kiju Konno
    Kiju Konno
    Department of Medicinal Chemistry, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo 101-0062, Japan
    More by Kiju Konno
  • Ai Himeno
    Ai Himeno
    Institute for Frontier Life and Medical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan
    More by Ai Himeno
  • Ami Masuda
    Ami Masuda
    Department of Medicinal Chemistry, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo 101-0062, Japan
    More by Ami Masuda
  • Tingting Yang
    Tingting Yang
    Department of Medicinal Chemistry, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo 101-0062, Japan
  • Kohei Takahashi
    Kohei Takahashi
    Department of Medicinal Chemistry, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo 101-0062, Japan
  • Yusuke Ishida
    Yusuke Ishida
    Department of Medicinal Chemistry, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo 101-0062, Japan
  • Nami Ohashi
    Nami Ohashi
    Department of Medicinal Chemistry, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo 101-0062, Japan
    More by Nami Ohashi
  • Takeo Kuwata
    Takeo Kuwata
    The Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto 860-0811, Japan
    More by Takeo Kuwata
  • Kaho Matsumoto
    Kaho Matsumoto
    The Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto 860-0811, Japan
  • Kazuhisa Yoshimura
    Kazuhisa Yoshimura
    Institute of Public Health, Bureau of Social Welfare and Public Health, Tokyo Metropolitan Government, Shinjuku-ku, Tokyo, 169-0073, Japan
  • Hiromi Sakawaki
    Hiromi Sakawaki
    Institute for Frontier Life and Medical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan
  • Tomoyuki Miura
    Tomoyuki Miura
    Institute for Frontier Life and Medical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan
  • Shigeyoshi Harada
    Shigeyoshi Harada
    AIDS Research Center, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan
  • Shuzo Matsushita
    Shuzo Matsushita
    The Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto 860-0811, Japan
  • , and 
  • Hirokazu Tamamura*
    Hirokazu Tamamura
    Department of Medicinal Chemistry, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo 101-0062, Japan
    *Email: [email protected]. Phone: +81-3-5280-8036.
Cite this: J. Med. Chem. 2021, 64, 3, 1481–1496
Publication Date (Web):January 26, 2021
https://doi.org/10.1021/acs.jmedchem.0c01153
Copyright © 2021 American Chemical Society

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    Abstract

    Abstract Image

    CD4 mimics are small molecules that inhibit the interaction of gp120 with CD4. We have developed several CD4 mimics. Herein, hybrid molecules consisting of CD4 mimics with a long alkyl chain or a PEG unit attached through a self-cleavable linker were synthesized. In anti-HIV activity, modification with a PEG unit appeared to be more suitable than modification with a long alkyl chain. Thus, hybrid molecules of CD4 mimics, with PEG units attached through an uncleavable linker, were developed and showed high anti-HIV activity and low cytotoxicity. In investigation of pharmacokinetics in a rhesus macaque, a hybrid compound had a more effective PK profile than that of the parent compound, and intramuscular injection was a more useful administration route to maintain the high blood concentration of the CD4 mimic than intravenous injection. The presented hybrid molecules of CD4 mimics with a PEG unit would be practically useful when combined with a neutralizing antibody.

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.0c01153.

    • Experimental procedures of compound synthesis including characterization data, a calibration curve of YIR-821·2TFA used to calculate PK in a rhesus macaque, degradation experiments of the hybrid molecule 45 in the PBS solution (pH 7.4) at 37 °C, a calibration curve of the hybrid molecule 58·2TFA used to calculate PK in a rhesus macaque by iv injection, a calibration curve of 58·2TFA used to calculate PK in a rhesus macaque by im injection, the structures of YIR-821 and compound 58 docked in gp120, HPLC analysis of evaluation of the biological stability of compound 58·2TFA treated with human liver microsomes, FACS analysis of EGFP and HIV-1 JR-FL envelope (Env) expressing HEK293T cells treated with anti-CD4i antibodies, and inhibition of gp120-CD4 binding by compound 58 and YIR-821 (PDF)

    • Molecular formula strings of 222, 24, 30, 32, 35, 36, 3846, 49, 50, 54, 58, and 62 (CSV)

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    Cited By

    This article is cited by 9 publications.

    1. Violeta Marković, Anna Szczepańska, Łukasz Berlicki. Antiviral Protein–Protein Interaction Inhibitors. Journal of Medicinal Chemistry 2024, 67 (5) , 3205-3231. https://doi.org/10.1021/acs.jmedchem.3c01543
    2. Takuya Kobayakawa, Masaru Yokoyama, Kohei Tsuji, Sayaka Boku, Masaki Kurakami, Masayuki Fujino, Takahiro Ishii, Yutaro Miura, Soshi Nishimura, Kouki Shinohara, Kenichi Yamamoto, Peter Bolah, Osamu Kotani, Tsutomu Murakami, Hironori Sato, Hirokazu Tamamura. Development of Small-Molecule Anti-HIV-1 Agents Targeting HIV-1 Capsid Proteins. Chemical and Pharmaceutical Bulletin 2024, 72 (1) , 41-47. https://doi.org/10.1248/cpb.c23-00618
    3. Kaho Matsumoto, Takeo Kuwata, William D. Tolbert, Jonathan Richard, Shilei Ding, Jérémie Prévost, Shokichi Takahama, George P. Judicate, Takamasa Ueno, Hirotomo Nakata, Takuya Kobayakawa, Kohei Tsuji, Hirokazu Tamamura, Amos B. Smith, Marzena Pazgier, Andrés Finzi, Shuzo Matsushita, . Characterization of a Novel CD4 Mimetic Compound YIR-821 against HIV-1 Clinical Isolates. Journal of Virology 2023, 97 (1) https://doi.org/10.1128/jvi.01638-22
    4. Takuya Kobayakawa, Masaru Yokoyama, Kohei Tsuji, Masayuki Fujino, Masaki Kurakami, Takato Onishi, Sayaka Boku, Takahiro Ishii, Yutaro Miura, Kouki Shinohara, Yuki Kishihara, Nami Ohashi, Osamu Kotani, Tsutomu Murakami, Hironori Sato, Hirokazu Tamamura. Low-molecular-weight anti-HIV-1 agents targeting HIV-1 capsid proteins. RSC Advances 2023, 13 (3) , 2156-2167. https://doi.org/10.1039/D2RA06837K
    5. Kanako Matsuura, Mizuki Yamaura, Hiromi Sakawaki, Ai Himeno, Yalcin Pisil, Takuya Kobayakawa, Kohei Tsuji, Hirokazu Tamamura, Shuzo Matsushita, Tomoyuki Miura. Sensitivity to a CD4 mimic of a consensus clone of monkey-adapted CCR5-tropic SHIV-MK38C. Virology 2023, 578 , 171-179. https://doi.org/10.1016/j.virol.2022.12.004
    6. Rongyi Wang, Kohei Tsuji, Takuya Kobayakawa, Yishan Liu, Kazuhisa Yoshimura, Shuzo Matsushita, Shigeyoshi Harada, Hirokazu Tamamura. Hybrids of small CD4 mimics and gp41-related peptides as dual-target HIV entry inhibitors. Bioorganic & Medicinal Chemistry 2022, 76 , 117083. https://doi.org/10.1016/j.bmc.2022.117083
    7. Paolo Governa, Fabrizio Manetti. Recent research results have converted gp120 binders to a therapeutic option for the treatment of HIV-1 infection. A medicinal chemistry point of view. European Journal of Medicinal Chemistry 2022, 229 , 114078. https://doi.org/10.1016/j.ejmech.2021.114078
    8. Kohei Tsuji, Takuya Kobayakawa, Kiju Konno, Ami Masuda, Kohei Takahashi, Nami Ohashi, Kazuhisa Yoshimura, Takeo Kuwata, Shuzo Matsushita, Shigeyoshi Harada, Hirokazu Tamamura. Exploratory studies on soluble small molecule CD4 mimics as HIV entry inhibitors. Bioorganic & Medicinal Chemistry 2022, 56 , 116616. https://doi.org/10.1016/j.bmc.2022.116616
    9. Ildar R. Iusupov, Francesca Curreli, Evgeniy A. Spiridonov, Pavel O. Markov, Shahad Ahmed, Dmitry S. Belov, Ekaterina V. Manasova, Andrea Altieri, Alexander V. Kurkin, Asim K. Debnath. Design of gp120 HIV-1 entry inhibitors by scaffold hopping via isosteric replacements. European Journal of Medicinal Chemistry 2021, 224 , 113681. https://doi.org/10.1016/j.ejmech.2021.113681

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