MolPharm xPharm- The Comprehensive Pharmacology Reference

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
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
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Sastry, J. K.
Right arrow Articles by Farquhar, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sastry, J. K.
Right arrow Articles by Farquhar, D.

Membrane-permeable dideoxyuridine 5'-monophosphate analogue inhibits human immunodeficiency virus infection

JK Sastry, PN Nehete, S Khan, BJ Nowak, W Plunkett, RB Arlinghaus and D Farquhar

Department of Molecular Pathology, University of Texas M. D. Anderson Cancer Center, Houston 77030.

2',3'-Dideoxyuridine (ddU) is ineffective at controlling human immunodeficiency virus type 1 (HIV-1) infection in human T cells, because it is not biotransformed to the active 5'-triphosphate. The metabolic block resides in the poor substrate affinity of ddU for cellular nucleoside kinases. This problem cannot be overcome by supplying the preformed nucleotides, because such compounds are unable to penetrate cells. To circumvent the requirement of ddU for enzymic phosphorylation, we have prepared bis(pivaloyloxymethyl) 2',3'- dideoxyuridine 5'-monophosphate (piv2 ddUMP), as a potential membrane- permeable prodrug of ddUMP, and investigated its metabolism and anti- HIV activity in two human T cell lines, one with wild-type thymidine kinase activity (MT-4) and the other deficient in thymidine kinase activity (CEM-tk-). The 5'-mono-, di-, and triphosphates of ddU were formed in both cell lines after exposure to piv2-ddUMP. In contrast, phosphorylated metabolites were not observed in cells treated with ddU or ddUMP alone. piv2-ddUMP also reduced the cytopathic effects of HIV-1 in MT-4 cells (ED50, 4.75 microM) and inhibited virus production in culture fluid (ED50, 20 microM). In addition, piv2-ddUMP protected CEM- tk- cells from HIV-1 infection, as demonstrated by inhibition of intracellular p24 antigen levels (ED50, 3 microM) and reverse transcriptase activity in culture medium (Ed50, 2.5 microM). Based on these findings, we propose that the "masked nucleotide" strategy may make available for development nucleoside analogues hitherto considered inactive because of failure to undergo biotransformation to the corresponding 5'-monophosphates. Moreover, by circumventing metabolic dependency on nucleoside kinases, the strategy may overcome acquired resistance to nucleoside analogues caused by the loss or depletion of nucleoside kinases.

Volume 41, Issue 3, pp. 441-445, 03/01/1992
Copyright © 1992 by American Society for Pharmacology and Experimental Therapeutics




This article has been cited by other articles:


Home page
 J. Biol. Chem.Home page
W. H. G. Laux, P. Pande, I. Shoshani, J. Gao, V. Boudou-Vivet, G. Gosselin, and R. A. Johnson
Pro-nucleotide Inhibitors of Adenylyl Cyclases in Intact Cells
J. Biol. Chem., April 2, 2004; 279(14): 13317 - 13332.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
T. Jiang, G. Sweeney, M. T. Rudolf, A. Klip, A. Traynor-Kaplan, and R. Y. Tsien
Membrane-permeant Esters of Phosphatidylinositol 3,4,5-Trisphosphate
J. Biol. Chem., May 1, 1998; 273(18): 11017 - 11024.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 1992 by the American Society for Pharmacology and Experimental Therapeutics