Activity against Human Immunodeficiency Virus Type 1, Intracellular Metabolism, and Effects on Human DNA Polymerases of 4′-Ethynyl-2-Fluoro-2′-Deoxyadenosine

cells were exposed to 0.1 M[ 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 M[ 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 17 and 3 h, respectively. When MT-4 cells were cultured with 0.01 M EFdA for 24 h, thoroughly washed to remove EFdA, further cultured without EFdA for various periods of time, exposed to HIV-1NL4-3, 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 M AZT were 55 and 9.2%, respectively. The 50% inhibitory concentration values of EFdA-TP against human polymerases , , and were >100 M, >100 M, and 10 M, respectively, while those of ddA-TP were >100 M, 0.2 M, and 0.2 M, 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.