Modulation of Metabolism and Anti-HIV-1 Activity of Purine 2′,3′-Dideoxynucleosides by IMP Dehydrogenase Inhibitors

Abstract

The dideoxynucleosides (ddNs) are having a substantial impact on the treatment of the human immunodeficiency syndrome (AIDS). The purine 2′,3′-dideoxyadenosine and its deaminated product 2′,3′-dideoxyinosine are potent inhibitors of human immunodeficiency virus (HIV) in human T lymphocytes and monocytes/macrophages (1,2). The anti-HIV effects of these drugs are mediated by conversion to the 5′-triphosphate ddATP. This triphosphate has been shown to act as both an inhibitor and substrate of HIV reverse transcriptase (3). The basis for the selectivity of ddI against HIV replication is related to the finding that its active metabolite ddATP binds more efficiently to reverse transcriptase than any of the cellular DNA polymerases (4). Although ddNs differ only slightly from their natural counterparts, their metabolism in cells differ substantially from that of the normal nucleosides. This diversity has manifested itself as differences in both antiviral potency and toxicity. Thus, these results imply a critical role for the anabolic pathways in determining the antiviral effectiveness of nucleoside analogs in anti-HIV therapy.