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
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
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 Dutschman, G. E.
Right arrow Articles by Cheng, Y.-C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Dutschman, G. E.
Right arrow Articles by Cheng, Y.-C.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, July 1998, p. 1799-1804, Vol. 42, No. 7
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Metabolism of 2',3'-Dideoxy-2',3'-Didehydro-beta -L(-)-5-Fluorocytidine and Its Activity in Combination with Clinically Approved Anti-Human Immunodeficiency Virus beta -D(+) Nucleoside Analogs In Vitro

Ginger E. Dutschman, Edward G. Bridges, Shwu-Huey Liu, Elizabeth Gullen, Xin Guo, Marina Kukhanova, and Yung-Chi Cheng*

Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520

Received 14 November 1997/Returned for modification 21 February 1998/Accepted 10 April 1998

2',3'-Dideoxy-2',3'-didehydro-beta -L(-)-5-fluorocytidine [L(-)Fd4C] has been reported to be a potent inhibitor of the human immunodeficiency virus (HIV) in cell culture. In the present study the antiviral activity of this compound in two-drug combinations and its intracellular metabolism are addressed. The two-drug combination of L(-)Fd4C plus 2',3'-didehydro-2',3'-dideoxythymidine (D4T, or stavudine) or 3'-azido-3'-deoxythymidine (AZT, or zidovudine) synergistically inhibited replication of HIV in vitro. Additive antiviral activity was observed with L(-)Fd4C in combination with 2',3'-dideoxycytidine (ddC, or zalcitabine) or 2',3'-dideoxyinosine (ddI, or didanosine). This beta -L(-) nucleoside analog has no activity against mitochondrial DNA synthesis at concentrations up to 10 µM. As we previously reported for other beta -L(-) nucleoside analogs, L(-)Fd4C could protect against mitochondrial toxicity associated with D4T, ddC, and ddI. Metabolism studies showed that this drug is converted intracellularly to its mono-, di-, and triphosphate metabolites. The enzyme responsible for monophosphate formation was identified as cytoplasmic deoxycytidine kinase, and the Km is 100 µM. L(-)Fd4C was not recognized in vitro by human mitochondrial deoxypyrimidine nucleoside kinase. Also, L(-)Fd4C was not a substrate for deoxycytidine deaminase. L(-)Fd4C 5'-triphosphate served as an alternative substrate to dCTP for incorporation into DNA by HIV reverse transcriptase. The favorable anti-HIV activity and protection from mitochondrial toxicity by L(-)Fd4C in two-drug combinations favors the further development of L(-)Fd4C as an anti-HIV agent.

* Corresponding author. Mailing address: Department of Pharmacology, Yale University School of Medicine, 333 Cedar St., P.O. Box 802066, New Haven, CT 06520-8066. Phone: (203) 785-7118. Fax: (203) 785-7129. E-mail: cheng.lab{at}yale.edu.

Antimicrobial Agents and Chemotherapy, July 1998, p. 1799-1804, Vol. 42, No. 7
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Wang, X., Tanaka, H., Baba, M., Cheng, Y.-c. (2009). Retention of Metabolites of 2',3'-Didehydro-3'-Deoxy-4'-Ethynylthymidine, a Novel Anti-Human Immunodeficiency Virus Type 1 Thymidine Analog, in Cells. Antimicrob. Agents Chemother. 53: 3317-3324 [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]  
  • Hu, R., Li, L., Degreve, B., Dutschman, G. E., Lam, W., Cheng, Y.-C. (2005). Behavior of Thymidylate Kinase toward Monophosphate Metabolites and Its Role in the Metabolism of 1-(2'-Deoxy-2'-Fluoro-{beta}-L-Arabinofuranosyl)-5-Methyluracil (Clevudine) and 2',3'-Didehydro-2',3'-Dideoxythymidine in Cells. Antimicrob. Agents Chemother. 49: 2044-2049 [Abstract] [Full Text]  
  • Dutschman, G. E., Grill, S. P., Gullen, E. A., Haraguchi, K., Takeda, S., Tanaka, H., Baba, M., Cheng, Y.-C. (2004). Novel 4'-Substituted Stavudine Analog with Improved Anti-Human Immunodeficiency Virus Activity and Decreased Cytotoxicity. Antimicrob. Agents Chemother. 48: 1640-1646 [Abstract] [Full Text]  
  • Krishnan, P., Gullen, E. A., Lam, W., Dutschman, G. E., Grill, S. P., Cheng, Y.-c. (2003). Novel Role of 3-Phosphoglycerate Kinase, a Glycolytic Enzyme, in the Activation of L-Nucleoside Analogs, a New Class of Anticancer and Antiviral Agents. J. Biol. Chem. 278: 36726-36732 [Abstract] [Full Text]  
  • Krishnan, P., Fu, Q., Lam, W., Liou, J.-Y., Dutschman, G., Cheng, Y.-C. (2002). Phosphorylation of Pyrimidine Deoxynucleoside Analog Diphosphates. SELECTIVE PHOSPHORYLATION OF L-NUCLEOSIDE ANALOG DIPHOSPHATES BY 3-PHOSPHOGLYCERATE KINASE. J. Biol. Chem. 277: 5453-5459 [Abstract] [Full Text]  
  • White, A. J (2001). Mitochondrial toxicity and HIV therapy. Sex. Transm. Infect. 77: 158-173 [Abstract] [Full Text]  
  • Kira, T., Grill, S. P., Dutschman, G. E., Lin, J.-S., Qu, F., Choi, Y., Chu, C. K., Cheng, Y.-C. (2000). Anti-Epstein-Barr Virus (EBV) Activity of beta -L-5-Iododioxolane Uracil Is Dependent on EBV Thymidine Kinase. Antimicrob. Agents Chemother. 44: 3278-3284 [Abstract] [Full Text]  
  • Li, L., Dutschman, G. E., Gullen, E. A., Tsujii, E., Grill, S. P., Choi, Y., Chu, C. K., Cheng, Y.-c. (2000). Metabolism and Mode of Inhibition of Varicella-Zoster Virus by L-beta -5-Bromovinyl-(2-hydroxymethyl)-(1,3-dioxolanyl)uracil Is Dependent on Viral Thymidine Kinase. Mol. Pharmacol. 58: 1109-1114 [Abstract] [Full Text]  
  • Pelicano, H., Kukhanova, M., Cheng, Y.-C. (2000). Excision of beta -D- and beta -L-Nucleotide Analogs from DNA by the Human Cytosolic 3'-to-5' Exonuclease. Mol. Pharmacol. 57: 1051-1055 [Abstract] [Full Text]  
  • Le Guerhier, F., Pichoud, C., Guerret, S., Chevallier, M., Jamard, C., Hantz, O., Li, X.-Y., Chen, S.-H., King, I., Trepo, C., Cheng, Y.-C., Zoulim, F. (2000). Characterization of the Antiviral Effect of 2',3'-Dideoxy-2', 3'-Didehydro-beta -L-5-Fluorocytidine in the Duck Hepatitis B Virus Infection Model. Antimicrob. Agents Chemother. 44: 111-122 [Abstract] [Full Text]  
  • Zhu, Y.-L., Dutschman, G. E., Liu, S.-H., Bridges, E. G., Cheng, Y.-C. (1998). Anti-Hepatitis B Virus Activity and Metabolism of 2',3'-Dideoxy-2',3'-Didehydro-beta -L(-)-5-Fluorocytidine. Antimicrob. Agents Chemother. 42: 1805-1810 [Abstract] [Full Text]  
  • Chou, K.-M., Kukhanova, M., Cheng, Y.-C. (2000). A Novel Action of Human Apurinic/Apyrimidinic Endonuclease. EXCISION OF L-CONFIGURATION DEOXYRIBONUCLEOSIDE ANALOGS FROM THE 3' TERMINI OF DNA. J. Biol. Chem. 275: 31009-31015 [Abstract] [Full Text]  


Copyright © 2010 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»