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Antimicrobial Agents and Chemotherapy, August 2007, p. 2701-2708, Vol. 51, No. 8
0066-4804/07/$08.00+0     doi:10.1128/AAC.00277-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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

Department of Infectious Diseases,¹ Department of Hematology, Kumamoto University School of Medicine, Kumamoto 860-8556, Japan,² Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892,³ Laboratory of Virus Immunology, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan,⁴ Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520,⁵ Biochemicals Division, Yamasa Corporation, Chosi 288-0056, Japan⁶

Received 23 February 2007/ Returned for modification 13 April 2007/ Accepted 24 May 2007

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 µM [³H]EFdA or [³H]3'-azido-2',3'-dideoxythymidine (AZT) for 6 h, the intracellular EFdA-triphosphate (TP) level was 91.6 pmol/10⁹ cells, while that of AZT was 396.5 pmol/10⁹ cells. When CEM cells were exposed to 10 µM [³H]EFdA, the amount of EFdA-TP increased by 22-fold (2,090 pmol/10⁹ cells), while the amount of [³H]AZT-TP increased only moderately by 2.4-fold (970 pmol/10⁹ 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 µM 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 µM AZT were 55 and 9.2%, respectively. The 50% inhibitory concentration values of EFdA-TP against human polymerases , ß, and were >100 µM, >100 µM, and 10 µM, respectively, while those of ddA-TP were >100 µM, 0.2 µM, and 0.2 µM, 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.

Published ahead of print on 4 June 2007.

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