1. Inhibition of multidrug-resistant HIV-1 by interference with cellular S-adenosylmethionine decarboxylase activity.
- Author
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Schäfer B, Hauber I, Bunk A, Heukeshoven J, Düsedau A, Bevec D, and Hauber J
- Subjects
- Adenosylmethionine Decarboxylase drug effects, Adenosylmethionine Decarboxylase metabolism, Amidines toxicity, Antibodies, Viral metabolism, Cell Line, Cell Survival drug effects, DNA Primers chemistry, Drug Resistance, Viral drug effects, Enzyme Inhibitors toxicity, Genes, rev drug effects, Humans, Indans toxicity, Peptide Initiation Factors drug effects, Polymerase Chain Reaction methods, RNA-Binding Proteins drug effects, Transcriptional Activation drug effects, Eukaryotic Translation Initiation Factor 5A, Adenosylmethionine Decarboxylase antagonists & inhibitors, Amidines pharmacology, Enzyme Inhibitors pharmacology, HIV-1 drug effects, Indans pharmacology, Virus Replication drug effects
- Abstract
S-adenosylmethionine decarboxylase (SAMDC), a key enzyme in polyamine biosynthesis, can be specifically inhibited by the experimental drug SAM486A. The pharmaceutical interference with SAMDC activity results in the depletion of the intracellular pool of spermidine and spermine. In particular, low spermidine levels compromise hypusine modification and, thereby, activation of eukaryotic initiation factor 5A (eIF-5A), which is a cellular cofactor of the essential human immunodeficiency virus type 1 (HIV-1) regulatory protein Rev. In the present study, we show that SAM486A efficiently suppresses HIV-1 replication, including the replication of viruses that are resistant to multiple reverse transcriptase and protease inhibitors. At drug concentrations that efficiently inhibit the formation of progeny viruses, no toxic effects of SAM486A on cellular metabolism are observed. It is demonstrated that the antiretroviral effect of SAM486A is based on the fact that Rev activity is severely compromised in drug-treated cells. Thus, inhibition of cellular SAMDC activity may provide a novel strategy to achieve suppression of otherwise drug-resistant viruses.
- Published
- 2006
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