Soluble-type small-molecule CD4 mimics as HIV entry inhibitors

Bioorg Med Chem Lett. 2019 Mar 1;29(5):719-723. doi: 10.1016/j.bmcl.2019.01.011. Epub 2019 Jan 11.

Abstract

Several small molecule CD4 mimics have been reported previously as HIV-1 entry inhibitors, which block the interaction between the Phe43 cavity of HIV-1 gp120 and the host CD4. Known CD4 mimics such as NBD-556 possess significant anti-HIV activity but are less soluble in water, perhaps due to their hydrophobic aromatic ring-containing structures. Compounds with a pyridinyl group in place of the phenyl group in these molecules have been designed and synthesized in an attempt to increase the hydrophilicity. Some of these new CD4 mimics, containing a tetramethylpiperidine ring show significantly higher water solubility than NBD-556 and have high anti-HIV activity and synergistic anti-HIV activity with a neutralizing antibody. The CD4 mimic that has a cyclohexylpiperidine ring and a 6-fluoropyridin-3-yl ring has high anti-HIV activity and no significant cytotoxicity. The present results will be useful in the future design and development of novel soluble-type molecule CD4 mimics.

Keywords: Anti-HIV; CD4 mimic; Pyridinyl group; Virus entry inhibitor; Water solubility.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Neutralizing / immunology
  • CD4 Antigens / chemistry*
  • HIV Fusion Inhibitors / chemistry
  • HIV Fusion Inhibitors / pharmacology*
  • HIV-1 / immunology
  • HIV-1 / physiology*
  • Humans
  • Molecular Mimicry*
  • Small Molecule Libraries / chemistry*
  • Solubility
  • Structure-Activity Relationship

Substances

  • Antibodies, Neutralizing
  • CD4 Antigens
  • HIV Fusion Inhibitors
  • Small Molecule Libraries