Mechanism of action and resistant profile of anti-HIV-1 coumarin derivatives

Virology. 2005 Feb 20;332(2):623-8. doi: 10.1016/j.virol.2004.11.033.


Dicamphanoyl khellactone (DCK) is a coumarin derivative that can potently inhibit HIV-1 replication. DCK does not inhibit RNA-dependent DNA synthesis. However, an HIV reverse transcriptase (RT) inhibitor-resistant strain, HIV-1/RTMDR1, is resistant to DCK. Thus, it is possible that HIV-1 RT is the target of DCK. To test this possibility, DCK-resistant viruses were selected in the presence of DCK. Our results indicate that a single amino acid mutation, E138K in HIV-1 RT, is sufficient to confer DCK resistance. Interestingly, a DCK derivative, 3'R,4'R-Di-O-(-)-camphanoyl-2-ethyl-2',2'-dimethyldihydropyrano[2,3-f]chromone (DCP8), is effective against HIV-1/RTMDR1. However, the DCK-escape virus carrying the E138K mutation remains resistant to DCP8. Since DCK did not inhibit the RNA-dependent DNA polymerase activity of HIV-1 RT when using poly-rA or poly-rC as template, we evaluated the effect of DCK on the DNA-dependent DNA polymerase activity of HIV-1 RT. Our results indicate that DCK can inhibit the DNA-dependent DNA polymerase activity of HIV-1 RT. In conclusion, DCK is a unique HIV-1 RT inhibitor that inhibits the DNA-dependent DNA polymerase activity. In contrast, DCK did not significantly affect the RNA-dependent DNA polymerase activity when poly-rA or poly-rC was used as templates. An E138K mutation in the non-nucleoside RT inhibitors (NNRTIs) binding pocket of HIV-1 RT confers resistance to DCK and its chromone derivative, DCP8.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Anti-HIV Agents / pharmacology*
  • Anti-HIV Agents / therapeutic use
  • Camphor / analogs & derivatives*
  • Camphor / pharmacology*
  • Cell Line
  • Coumarins / pharmacology*
  • Coumarins / therapeutic use
  • Drug Resistance, Viral*
  • HIV-1 / drug effects*
  • HIV-1 / pathogenicity
  • HIV-1 / physiology
  • Humans
  • Lactones / pharmacology*
  • Reverse Transcriptase Inhibitors / pharmacology
  • Virus Replication / drug effects


  • 3'R,4'R-di-O-(-)-camphanoyl-(+)-cis-khellactone
  • Anti-HIV Agents
  • Coumarins
  • Lactones
  • Reverse Transcriptase Inhibitors
  • Camphor