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  3. Exploratory studies on soluble small molecule CD4 mimics as HIV entry inhibitors

Exploratory studies on soluble small molecule CD4 mimics as HIV entry inhibitors

  • Bioorg Med Chem. 2022 Feb 15;56:116616. doi: 10.1016/j.bmc.2022.116616.
Kohei Tsuji 1,  Takuya Kobayakawa 1,  Kiju Konno 1,  Ami Masuda 1,  Kohei Takahashi 1,  Nami Ohashi 1,  Kazuhisa Yoshimura 2,  Takeo Kuwata 3,  Shuzo Matsushita 3,  Shigeyoshi Harada 4,  Hirokazu Tamamura 5
Affiliations

Affiliations

  • 1 Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
  • 2 Institute of Public Health, Bureau of Social Welfare and Public Health, Tokyo Metropolitan Government, Shinjuku-ku, Tokyo 169-0073, Japan.
  • 3 The Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto 860-0811, Japan.
  • 4 AIDS Research Center, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan. Electronic address: shigeh@nih.go.jp.
  • 5 Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo 101-0062, Japan. Electronic address: tamamura.mr@tmd.ac.jp.
PMID: 35063895 DOI: 10.1016/j.bmc.2022.116616
Abstract

Several small molecule CD4 mimics, which inhibit the interaction of gp120 with CD4, have been developed. Original CD4 mimics such as NBD-556, which has an aromatic ring, an oxalamide linker and a piperidine moiety, possess significant anti-HIV activity but with their hydrophobic aromatic ring-containing structures are poorly soluble in water. We have developed derivatives with a halopyridinyl group in place of the phenyl group, such as KKN-134, and found them to have excellent aqueous solubility. Other leads that were examined are YIR-821, a compound with a cyclohexane group in a spiro attachment to a piperidine ring and a guanidino group on the piperidine nitrogen atom, and its PEGylated derivative, TKB-002. YIR-821 and TKB-002 retain potent anti-HIV activity. Here, new CD4 mimics, in which the phenyl group was replaced by a halopyridinyl group with the halogen atoms in different positions, their derivatives without a cyclohexane group on the piperidine ring and their hybrid molecules with PEG units were designed and synthesized. Some of these compounds show significantly higher aqueous solubility with maintenance of certain levels of anti-HIV activity. The present data should be useful in the future design of CD4 mimic molecules.

Keywords

Aqueous solubility; CD4 mimic; Halopyridinyl group; anti-HIV.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-146973
    HIV抑制剂
    HIV
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