Back to Search
Start Over
Enhanced stimulation by ribavirin of the 5'-phosphorylation and anti-human immunodeficiency virus activity of purine 2'-beta-fluoro-2',3'-dideoxynucleosides.
- Source :
-
Molecular pharmacology [Mol Pharmacol] 1993 Sep; Vol. 44 (3), pp. 519-23. - Publication Year :
- 1993
-
Abstract
- The purine dideoxynucleosides 2'-beta-fluoro-2',3'-dideoxyadenosine (2'-beta-F-ddAdo), 2'-beta-fluoro-2',3'-dideoxyinosine, and 2'-beta-fluoro-2',3'-dideoxyguanosine (2'-beta-F-ddGuo) are active inhibitors of the replication of the human immunodeficiency virus (HIV) in the ATH8 assay system, with 2'-beta-F-ddAdo and 2'-beta-fluoro-2',3'- dideoxyinosine showing activity and potency equivalent to those of their respective parent compounds, 2',3'-dideoxyadenosine (ddAdo) and 2',3'-dideoxyinosine. Because inhibitors of IMP dehydrogenase such as ribavirin and tiazofurin stimulate the 5'-phosphorylation and consequently the anti-HIV activity of the three nonfluorinated parent compounds (ddAdo, 2',3'-dideoxyinosine, and 2',3'-dideoxyguanosine), we have undertaken a study in MOLT-4 cells to determine whether a similar stimulatory effect is observed with their 2'-beta-fluorinated analogs. The 5'-phosphorylation of all the fluoro compounds was found to be greatly enhanced by low levels (10 microM) of either ribavirin or tiazofurin, with the greatest increase being seen with 2'-beta-F-ddAdo, where stimulation of the formation of the 5'-mono-, di-, and triphosphorylated nucleotides was approximately 20-fold, 6-fold, and 5-fold, respectively. These increases were approximately 3-fold greater than the increases seen with the nonfluorinated parent compound ddAdo. In the case of 2'-beta-F-ddGuo, the greatest stimulation (8-fold) was seen in the formation of the 5'-diphosphate. In parallel with the increased phosphorylation of 2'-beta-F-ddAdo and 2'-beta-F-ddGuo, the anti-HIV potency of these two compounds at the 5 microM level was approximately doubled in the presence of ribavirin (5 microM).
- Subjects :
- Didanosine analogs & derivatives
Didanosine pharmacology
Dideoxyadenosine analogs & derivatives
Dideoxyadenosine pharmacology
Dideoxynucleosides metabolism
Drug Synergism
Phosphorylation drug effects
Purine Nucleosides metabolism
Structure-Activity Relationship
Dideoxynucleosides pharmacology
HIV-1 drug effects
Purine Nucleosides pharmacology
Ribavirin pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0026-895X
- Volume :
- 44
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Molecular pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 8371712