Inhibitors of IMP dehydrogenase stimulate the phosphorylation of the anti-human immunodeficiency virus nucleosides 2',3'-dideoxyadenosine and 2',3'-dideoxyinosine.
2',3'-Dideoxyadenosine (ddAdo) and its deamination product 2',3'-dideoxyinosine (ddIno) (didanosine) inhibit the replication and infectivity of the human immunodeficiency virus (HIV) in a number of in vitro assay systems. Early clinical studies (phase I) have indicated a role for ddIno in the treatment of patients with severe HIV infection. In the present in vitro study, the formation in human T cells (MOLT-4, ATH8, and CCRF-CEM) of the pharmacologically active metabolite of ddIno and ddAdo, 2',3'-dideoxyadenosine-5'-triphosphate (ddATP), was found to be stimulated 2-4-fold by appropriate concentrations of inosinate dehydrogenase (IMPD) inhibitors such as ribavirin, tiazofurin, and mycophenolic acid. Concomitant with this increase in ddATP formation from ddIno was an increase in anti-HIV activity of this agent when it was combined with ribavirin in the ATH8 cell assay system and with tiazofurin in the MOLT-4 assay system. No change was noted in the intracellular concentration of the corresponding physiological deoxynucleoside-5'-triphosphate, dATP; positive correlation was observed, however, between the increase in ddATP formation from ddIno and the increase in intracellular IMP occurring as a consequence of IMPD inhibition. The results support the hypothesis that the stimulation of ddATP formation seen when ddIno is combined with ribavirin or other IMPD inhibitors is a consequence of an increased concentration of IMP, the major phosphate donor for the initial phosphorylation step in the anabolism of ddIno to ddATP, i.e., ddIno----ddIMP.
Laboratory of Medicinal Chemistry, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
N R
NR
Hartman
G S
GS
Ahluwalia
D A
DA
Cooney
H
H
Mitsuya
S
S
Kageyama
A
A
Fridland
S
S
Broder
D G
DG
Johns
D000998:Antiviral Agents / Q000494:pharmacology; D002478:Cells, Cultured; D002845:Chromatography; D016049:Didanosine / Q000378:metabolism*; D016048:Dideoxyadenosine / Q000378:metabolism*; D004357:Drug Synergism; D006678:HIV / Q000187:drug effects; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D007288:Inosine / Q000494:pharmacology; D007291:Inosine Monophosphate / Q000378:metabolism; D009711:Nucleotides / Q000302:isolation & purification / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D012254:Ribavirin / Q000494:pharmacology; D013268:Stimulation, Chemical
D000998:Antiviral Agents; D009711:Nucleotides; D007291:Inosine Monophosphate; D012254:Ribavirin; D016048:Dideoxyadenosine; D007288:Inosine; D007168:IMP Dehydrogenase; D016049:Didanosine