Activity against human immunodeficiency virus type 1, intracellular metabolism, and effects on human DNA polymerases of 4'-ethynyl-2-fluoro-2'-deoxyadenosine

Antimicrob Agents Chemother. 2007 Aug;51(8):2701-8. doi: 10.1128/AAC.00277-07. Epub 2007 Jun 4.


We examined the intracytoplasmic anabolism and kinetics of antiviral activity against human immunodeficiency virus type 1 (HIV-1) of a nucleoside reverse transcriptase inhibitor, 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), which has potent activity against wild-type and multidrug-resistant HIV-1 strains. When CEM cells were exposed to 0.1 microM [(3)H]EFdA or [(3)H]3'-azido-2',3'-dideoxythymidine (AZT) for 6 h, the intracellular EFdA-triphosphate (TP) level was 91.6 pmol/10(9) cells, while that of AZT was 396.5 pmol/10(9) cells. When CEM cells were exposed to 10 microM [(3)H]EFdA, the amount of EFdA-TP increased by 22-fold (2,090 pmol/10(9) cells), while the amount of [(3)H]AZT-TP increased only moderately by 2.4-fold (970 pmol/10(9) cells). The intracellular half-life values of EFdA-TP and AZT-TP were approximately 17 and approximately 3 h, respectively. When MT-4 cells were cultured with 0.01 microM EFdA for 24 h, thoroughly washed to remove EFdA, further cultured without EFdA for various periods of time, exposed to HIV-1(NL4-3), and cultured for an additional 5 days, the protection values were 75 and 47%, respectively, after 24 and 48 h with no drug incubation, while those with 1 microM AZT were 55 and 9.2%, respectively. The 50% inhibitory concentration values of EFdA-TP against human polymerases alpha, beta, and gamma were >100 microM, >100 microM, and 10 microM, respectively, while those of ddA-TP were >100 microM, 0.2 microM, and 0.2 microM, respectively. These data warrant further development of EFdA as a potential therapeutic agent for those patients who harbor wild-type HIV-1 and/or multidrug-resistant variants.

Publication types

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

MeSH terms

  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / metabolism
  • Anti-HIV Agents / pharmacology*
  • CD4-Positive T-Lymphocytes
  • Cells, Cultured
  • Culture Media
  • DNA-Directed DNA Polymerase / drug effects*
  • Deoxyadenosines / chemistry*
  • Deoxyadenosines / metabolism
  • Deoxyadenosines / pharmacology*
  • HIV-1 / drug effects*
  • Humans
  • Microbial Sensitivity Tests
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / metabolism
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Tritium / metabolism
  • Zidovudine / metabolism
  • Zidovudine / pharmacology


  • Anti-HIV Agents
  • Culture Media
  • Deoxyadenosines
  • Reverse Transcriptase Inhibitors
  • Tritium
  • Zidovudine
  • DNA-Directed DNA Polymerase