Enhanced stimulation by ribavirin of the 5'-phosphorylation and anti- human immunodeficiency virus activity of purine 2'-beta-fluoro-2',3'- dideoxynucleosides

DG Johns, GS Ahluwalia, DA Cooney, H Mitsuya and JS Driscoll

Laboratory of Medicinal Chemistry, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.

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).

Volume 44, Issue 3, pp. 519-523, 09/01/1993
Copyright © 1993 by American Society for Pharmacology and Experimental Therapeutics

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