Membrane-permeable dideoxyuridine 5'-monophosphate analogue inhibits human immunodeficiency virus infection
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 ki...
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Published in | Molecular pharmacology Vol. 41; no. 3; pp. 441 - 445 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Pharmacology and Experimental Therapeutics
01.03.1992
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Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0026-895X 1521-0111 |