Inhibitors of IMP dehydrogenase stimulate the phosphorylation of the antiviral nucleoside 2' ,3'-dideoxyguanosine.
The inosinate dehydrogenase (IMPD) inhibitors ribavirin, tiazofurin and mycophenolic acid were found to stimulate by as much as 20-fold the anabolism of the anti-HIV agent 2' ,3'dideoxyguanosine to its 5'-diphosphate (ddGDP) in a human T-cell culture system (Molt-4 cells). Stimulation of the further conversion to ddGTP (the active form of the drug) was lesser in magnitude but still highly significant (up to 4-fold at appropriate concentrations of ribavirin or tiazofurin). In parallel with these increases, the inhibitors also produced increases of up to 35-fold in IMP levels. These results support the proposal that the initial phosphorylation of ddGuo is catalyzed by a phosphotransferase (5'-nucleotidase) which utilizes IMP as its phosphate donor (Johnson and Fridland, [1989] Molec. Pharmacol. 36, 291-295). Concomitant with this increase in 5'-phosphorylation of ddGuo, an increase in its anti-HIV activity of up to 6.5-fold was observed when this agent was combined with ribavirin (5 microM) in the H9 [corrected] cell assay system.
Ahluwalia
G
G
Developmental Therapeutics Program, National Cancer Institute, NIH, Bethesda, MD 20892.
Cooney
D A
DA
Bondoc
L L
LL
Currens
M J
MJ
Ford
H
H
Johns
D G
DG
Mitsuya
H
H
Fridland
A
A
D000998:Antiviral Agents / Q000378:metabolism*; D002460:Cell Line; D015224:Dideoxynucleosides / Q000378:metabolism* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D007700:Kinetics; D009173:Mycophenolic Acid / Q000494:pharmacology*; D009711:Nucleotides / Q000302:isolation & purification; D010766:Phosphorylation; D012254:Ribavirin / Q000031:analogs & derivatives* / Q000494:pharmacology*
D000998:Antiviral Agents; D015224:Dideoxynucleosides; D009711:Nucleotides; D012254:Ribavirin; C050220:2',3'-dideoxyguanosine; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid; C033706:tiazofurin