title: Phosphorylation of triciribine is necessary for activity against HIV type 1.
abstract: Triciribine (TCN) is a tricyclic nucleoside with known antineoplastic and antiviral activity. It is a potent and selective inhibitor of HIV-1 and HIV-2, including strains known to be resistant to AZT or TIBO. TCN is phosphorylated to its 5'-monophosphate (TCN-P) by intracellular adenosine kinase (AK), but is not converted to di- or triphosphates. We now report that 5'-phosphorylation is requisite for the activity of TCN against HIV-1. CEM cells incubated with TCN at concentrations ranging from 0.1 to 330 microM gave intracellular TCN-P concentrations from 27 to 775 microM, respectively. There was no difference in the amount of intracellular TCN-P detected in uninfected compared with HIV-1-infected CEM cells. The antiviral effect of TCN against HIV-1 was strongly antagonized by the AK inhibitor 5-iodotubercidin (ITu). In contrast, TCN and ITu only exhibited additive cytotoxicity. The 5'-deoxy analog of TCN, which cannot be phosphorylated, had no antiviral effect against HIV-1 at a concentration more than 100 times higher than the IC50 of TCN. Similarly, TCN was not active against HIV-1 in an AK-deficient cell line (AA-2) at concentrations shown to inhibit the virus by >95% in CEM cells. Consistent with its AK-deficient phenotype, this cell line phosphorylated TCN to only 3% of the extent observed in CEM cells. We conclude that TCN must be phosphorylated to TCN-P for activity against HIV-1.
authors.affiliation: Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor 48109-1078, USA.
authors.forename: R G
authors.initials: RG
authors.lastname: Ptak
authors.forename: K Z
authors.initials: KZ
authors.lastname: Borysko
authors.forename: A R
authors.initials: AR
authors.lastname: Porcari
authors.forename: J L
authors.initials: JL
authors.lastname: Buthod
authors.forename: L E
authors.initials: LE
authors.lastname: Holland
authors.forename: C
authors.initials: C
authors.lastname: Shipman
authors.forename: L B
authors.initials: LB
authors.lastname: Townsend
authors.forename: J C
authors.initials: JC
authors.lastname: Drach
mesh_terms: D000073:Acenaphthenes; D000248:Adenosine Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D019380:Anti-HIV Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001711:Biotransformation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D019169:Jurkat Cells; D010766:Phosphorylation; D012263:Ribonucleosides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D012265:Ribonucleotides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000073:Acenaphthenes; D019380:Anti-HIV Agents; D004791:Enzyme Inhibitors; D012263:Ribonucleosides; D012265:Ribonucleotides; C023764:triciribine; C014205:triciribine phosphate; D000248:Adenosine Kinase