Inhibitors of IMP dehydrogenase stimulate the phosphorylation of the antiviral nucleoside 2′,3′-dideoxyguanosine
| Autor: | David A. Cooney, David G. Johns, Hiroaki Mitsuya, Laureano L. Bondoc, Harry Ford, Michael J. Currens, Arnold Fridland, Gurpreet S. Ahluwalia |
|---|---|
| Rok vydání: | 1990 |
| Předmět: |
Biophysics
Biology Antiviral Agents Biochemistry Cell Line Phosphotransferase IMP Dehydrogenase IMP dehydrogenase Ribavirin medicine Humans Nucleotide Phosphorylation Molecular Biology chemistry.chemical_classification Nucleotides Biological activity Cell Biology Mycophenolic Acid Dideoxynucleosides Kinetics chemistry Enzyme inhibitor HIV-1 biology.protein Nucleoside Tiazofurin medicine.drug |
| Zdroj: | Biochemical and Biophysical Research Communications. 171:1297-1303 |
| ISSN: | 0006-291X |
| DOI: | 10.1016/0006-291x(90)90827-a |
| Popis: | The inosinate dehydrogenase (IMPD) inhibitors ribavirin, tiazofurin and mycophenolic acid were found to stimulate by as much as 20-fold the anabolism of the anti-HIV agent 2' ,3'dideoxyguanosine to its 5'-diphosphate (ddGDP) in a human T-cell culture system (Molt-4 cells). Stimulation of the further conversion to ddGTP (the active form of the drug) was lesser in magnitude but still highly significant (up to 4-fold at appropriate concentrations of ribavirin or tiazofurin). In parallel with these increases, the inhibitors also produced increases of up to 35-fold in IMP levels. These results support the proposal that the initial phosphorylation of ddGuo is catalyzed by a phosphotransferase (5'-nucleotidase) which utilizes IMP as its phosphate donor (Johnson and Fridland, [1989] Molec. Pharmacol. 36, 291-295). Concomitant with this increase in 5'-phosphorylation of ddGuo, an increase in its anti-HIV activity of up to 6.5-fold was observed when this agent was combined with ribavirin (5 microM) in the H9 [corrected] cell assay system. |
| Databáze: | OpenAIRE |
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