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
  • 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.