2. Academic Validation
  3. Hybrids of Small-Molecule CD4 Mimics with Polyethylene Glycol Units as HIV Entry Inhibitors

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

  • J Med Chem. 2021 Feb 11;64(3):1481-1496. doi: 10.1021/acs.jmedchem.0c01153.
Takuya Kobayakawa 1,  Kohei Tsuji 1,  Kiju Konno 1,  Ai Himeno 2,  Ami Masuda 1,  Tingting Yang 1,  Kohei Takahashi 1,  Yusuke Ishida 1,  Nami Ohashi 1,  Takeo Kuwata 3,  Kaho Matsumoto 3,  Kazuhisa Yoshimura 4,  Hiromi Sakawaki 2,  Tomoyuki Miura 2,  Shigeyoshi Harada 5,  Shuzo Matsushita 3,  Hirokazu Tamamura 1
Affiliations

Affiliations

  • 1 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.
  • 2 Institute for Frontier Life and Medical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan.
  • 3 The Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto 860-0811, Japan.
  • 4 Institute of Public Health, Bureau of Social Welfare and Public Health, Tokyo Metropolitan Government, Shinjuku-ku, Tokyo, 169-0073, Japan.
  • 5 AIDS Research Center, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan.
PMID: 33497209 DOI: 10.1021/acs.jmedchem.0c01153
Abstract

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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