This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Feng, J. Y.
Right arrow Articles by Anderson, K. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Feng, J. Y.
Right arrow Articles by Anderson, K. S.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, April 2004, p. 1300-1306, Vol. 48, No. 4
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.4.1300-1306.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Relationship between Antiviral Activity and Host Toxicity: Comparison of the Incorporation Efficiencies of 2',3'-Dideoxy-5-Fluoro-3'-Thiacytidine-Triphosphate Analogs by Human Immunodeficiency Virus Type 1 Reverse Transcriptase and Human Mitochondrial DNA Polymerase

Joy Y. Feng,1 Eisuke Murakami,2 Suzana M. Zorca,2 Allison A. Johnson,3,{dagger} Kenneth A. Johnson,3 Raymond F. Schinazi,4 Phillip A. Furman,5 and Karen S. Anderson2*

Gilead Sciences, Durham, North Carolina 27707,1 Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520-8066,2 Institute of Cellular and Molecular Biology, University of Texas, Austin, Texas 78712,3 Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine/Veterans Administration Medical Center, Decatur, Georgia 30033,4 Pharmasset, Inc., Tucker, Georgia 300845

Received 6 August 2003/ Returned for modification 6 November 2003/ Accepted 18 December 2003

Emtricitabine [(-)FTC; (-)-ß-L-2'-3'-dideoxy-5-fluoro-3'-thiacytidine] is an oxathiolane nucleoside analog recently approved by the Food and Drug Administration for the treatment of human immunodeficiency virus (HIV). Structurally, (-)FTC closely resembles lamivudine [(-)3TC] except that the former is 5-fluorinated on the cytosine ring. In HIV-1 reverse transcriptase (RT) enzymatic assays, the triphosphate of (-)FTC [(-)FTC-TP] was incorporated into both DNA-DNA and DNA-RNA primer-templates nearly 3- and 10-fold more efficiently than (-)3TC-TP. Animal studies and clinical trial studies have demonstrated a favorable safety profile for (-)FTC. However, a detailed study of the incorporation of (-)FTC-TP by human mitochondrial DNA polymerase {gamma}, a host enzyme associated with nucleoside toxicity, is required for complete understanding of the molecular mechanisms of inhibition and toxicity. We studied the incorporation of (-)FTC-TP and its enantiomer (+)FTC-TP into a DNA-DNA primer-template by recombinant human mitochondrial DNA polymerase in a pre-steady-state kinetic analysis. (-)FTC-TP was incorporated 2.9 x 105-, 1.1 x 105-, 1.6 x 103-, 7.9 x 103-, and 100-fold less efficiently than dCTP, ddCTP, (+)3TC-TP, (+)FTC-TP, and (-)3TC-TP, respectively. The rate of removal of (-)FTC-MP from the corresponding chain-terminated 24-mer DNA by polymerase {gamma}'s 3'->5' exonuclease activity was equal to the removal of (+)FTC-MP, 2-fold slower than the removal of (-)3TC-MP and (+)3TC-MP, and 4.6-fold slower than the excision of dCMP. These results demonstrate that there are clear differences between HIV-1 RT and polymerase {gamma} in terms of preferences for substrate structure.

* Corresponding author. Mailing address: Department of Pharmacology, Yale University School of Medicine, 333 Cedar St., New Haven, CT 06520-8066. Phone: (203) 785-4526. Fax (203) 785-7670. E-mail: karen.anderson{at}yale.edu.

{dagger} Present address: National Cancer Institute, National Institutes of Health, Bethesda, MD 20850.

Antimicrobial Agents and Chemotherapy, April 2004, p. 1300-1306, Vol. 48, No. 4
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.4.1300-1306.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Hanes, J. W., Johnson, K. A. (2008). Exonuclease Removal of Dideoxycytidine (Zalcitabine) by the Human Mitochondrial DNA Polymerase. Antimicrob. Agents Chemother. 52: 253-258 [Abstract] [Full Text]  
  • Hanes, J. W., Johnson, K. A. (2007). A novel mechanism of selectivity against AZT by the human mitochondrial DNA polymerase. Nucleic Acids Res 35: 6973-6983 [Abstract] [Full Text]  
  • Paintsil, E., Dutschman, G. E., Hu, R., Grill, S. P., Lam, W., Baba, M., Tanaka, H., Cheng, Y.-C. (2007). Intracellular Metabolism and Persistence of the Anti-Human Immunodeficiency Virus Activity of 2',3'-Didehydro-3'-Deoxy-4'-Ethynylthymidine, a Novel Thymidine Analog. Antimicrob. Agents Chemother. 51: 3870-3879 [Abstract] [Full Text]  
  • Hanes, J. W., Zhu, Y., Parris, D. S., Johnson, K. A. (2007). Enzymatic Therapeutic Index of Acyclovir: VIRAL VERSUS HUMAN POLYMERASE {gamma} SPECIFICITY. J. Biol. Chem. 282: 25159-25167 [Abstract] [Full Text]  
  • Alexandre, J. A.C., Roy, B., Topalis, D., Pochet, S., Perigaud, C., Deville-Bonne, D. (2007). Enantioselectivity of human AMP, dTMP and UMP-CMP kinases. Nucleic Acids Res 0: gkm479v1-10 [Abstract] [Full Text]  
  • Nitanda, T., Wang, X., Kumamoto, H., Haraguchi, K., Tanaka, H., Cheng, Y.-C., Baba, M. (2005). Anti-Human Immunodeficiency Virus Type 1 Activity and Resistance Profile of 2',3'-Didehydro-3'-Deoxy-4'-Ethynylthymidine In Vitro. Antimicrob. Agents Chemother. 49: 3355-3360 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»