ENHANCEMENT BY 2'-DEOXYCOFORMYCIN OF THE 5'-PHOSPHORYLATION AND ANTI-HUMAN-IMMUNODEFICIENCY-VIRUS ACTIVITY OF 2',3'-DIDEOXYADENOSINE AND 2'-BETA-FLUORO-2',3'-DIDEOXYADENOSINE

The anti-human immunodeficiency virus agents 2',3'-dideoxyadenosine (d dAdo) and 2'-beta-fluoro-2',3'-dideoxyadenosine (2'-beta-F-ddAdo) are rapidly converted, both in vitro and in vivo, to the corresponding ino sine analogs by the widely distributed enzyme adenosine deaminase (EC 3.5.4.4). We have determined the effects of the potent adenosine deami nase inhibitor 2'-deoxy-coformycin (2'-dCF) on ddAdo and 2'-beta-F-ddA do metabolism in MOLT-4 cells and on ddAdo antiviral activity in the A TH8 test system. At levers as low as 5 nM in the incubation medium, 2' -dCF effectively blocks the extracellular deamination of both agents, thus permitting their rapid cellular uptake as the unchanged parent co mpounds, rather than as the less lipid-soluble 2',3'-dideoxyinosine or 2'-beta-fluoro-2',3'-dideoxyinosine. The result is a significant incr ease in intracellular levels of the pharmacologically active forms 2', 3' -dideoxyadenosine-5'-triphosphate and eta-fluoro-2',3'-dideoxyadeno sine-5'-triphosphate. The effect becomes maximal over the range of 50- 250 nM 2'-dCF and declines to control levels when extracellular 2'-dCF revels exceed 1 mu M. This decrease in ddAdo and 2'-beta-F-ddAdo phos phorylation with higher levels of the inhibitor appears to result from intracellular penetration of 2'-dCF and consequent inhibition of intr acellular deamination, a critical step in the activation of both agent s through the 5'-nucleotidase pathway. In anti-human immunodeficiency virus assays, a 2.2-fold increase in ddAdo antiviral potency was seen at 2'-dCF levels of 20 and 50 nM.