title: Activity against human immunodeficiency virus type 1, intracellular metabolism, and effects on human DNA polymerases of 4'-ethynyl-2-fluoro-2'-deoxyadenosine.
abstract: 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.
authors.affiliation: Department of Infectious, Kumamoto University School of Medicine, 1-1-1 Honjo, Kumamoto, Japan.
authors.forename: Hirotomo
authors.initials: H
authors.lastname: Nakata
authors.forename: Masayuki
authors.initials: M
authors.lastname: Amano
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Koh
authors.forename: Eiichi
authors.initials: E
authors.lastname: Kodama
authors.forename: Guangwei
authors.initials: G
authors.lastname: Yang
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Bailey
authors.forename: Satoru
authors.initials: S
authors.lastname: Kohgo
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hayakawa
authors.forename: Masao
authors.initials: M
authors.lastname: Matsuoka
authors.forename: Karen S
authors.initials: KS
authors.lastname: Anderson
authors.forename: Yung-Chi
authors.initials: YC
authors.lastname: Cheng
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mitsuya
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes; D002478:Cells, Cultured; D003470:Culture Media; D004259:DNA-Directed DNA Polymerase / Q000187:drug effects*; D003839:Deoxyadenosines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D014316:Tritium / Q000378:metabolism; D015215:Zidovudine / Q000378:metabolism / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D003470:Culture Media; D003839:Deoxyadenosines; D018894:Reverse Transcriptase Inhibitors; D014316:Tritium; D015215:Zidovudine; D004259:DNA-Directed DNA Polymerase