Identification of N-phenyl-N'-(2,2,6,6-tetramethyl-piperidin-4-yl)-oxalamides as a new class of HIV-1 entry inhibitors that prevent gp120 binding to CD4

Virology. 2005 Sep 1;339(2):213-25. doi: 10.1016/j.virol.2005.06.008.


We have identified two N-phenyl-N'-(2,2,6,6-tetramethyl-piperidin-4-yl)-oxalamide analogs as a novel class of human immunodeficiency virus type 1 (HIV-1) entry inhibitors that block the gp120-CD4 interaction, using database screening techniques. The lead compounds, NBD-556 and NBD-557, are small molecule organic compounds with drug-like properties. These compounds showed potent cell fusion and virus-cell fusion inhibitory activity at low micromolar levels. A systematic study showed that these compounds target viral entry by inhibiting the binding of HIV-1 envelope glycoprotein gp120 to the cellular receptor CD4 but did not inhibit reverse transcriptase, integrase, or protease, indicating that they do not target the later stages of the HIV-1 life cycle to inhibit HIV-1 infection. These compounds were equally potent inhibitors of both X4 and R5 viruses tested in CXCR4 and CCR5 expressing cell lines, respectively, indicating that their anti-HIV-1 activity is not dependent on the coreceptor tropism of the virus. A surface plasmon resonance study, which measures binding affinity, clearly demonstrated that these compounds bind to unliganded HIV-1 gp120 but not to the cellular receptor CD4. NBD-556 and NBD-557 were active against HIV-1 laboratory-adapted strains including an AZT-resistant strain and HIV-1 primary isolates, indicating that these compounds can potentially be further modified to become potent HIV-1 entry inhibitors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / isolation & purification
  • Anti-HIV Agents / pharmacology*
  • Binding, Competitive
  • CD4 Antigens / chemistry
  • CD4 Antigens / drug effects*
  • CD4 Antigens / metabolism
  • HIV Envelope Protein gp120 / metabolism*
  • HIV-1 / chemistry*
  • HIV-1 / physiology
  • Humans
  • Oxamic Acid / analogs & derivatives*
  • Oxamic Acid / chemistry
  • Oxamic Acid / pharmacology*
  • Protein Binding / drug effects
  • Protein Structure, Tertiary / drug effects
  • Receptors, HIV / antagonists & inhibitors*
  • Virus Replication / drug effects


  • Anti-HIV Agents
  • CD4 Antigens
  • HIV Envelope Protein gp120
  • Receptors, HIV
  • Oxamic Acid