Phosphorylation of triciribine is necessary for activity against HIV type 1

AIDS Res Hum Retroviruses. 1998 Oct 10;14(15):1315-22. doi: 10.1089/aid.1998.14.1315.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acenaphthenes
  • Adenosine Kinase / antagonists & inhibitors
  • Adenosine Kinase / metabolism
  • Anti-HIV Agents / pharmacokinetics
  • Anti-HIV Agents / pharmacology*
  • Biotransformation
  • Enzyme Inhibitors / pharmacology
  • HIV-1 / drug effects*
  • Humans
  • Jurkat Cells
  • Phosphorylation
  • Ribonucleosides / chemistry
  • Ribonucleosides / pharmacokinetics
  • Ribonucleosides / pharmacology*
  • Ribonucleotides / chemistry
  • Ribonucleotides / pharmacokinetics
  • Ribonucleotides / pharmacology*
  • Tumor Cells, Cultured


  • Acenaphthenes
  • Anti-HIV Agents
  • Enzyme Inhibitors
  • Ribonucleosides
  • Ribonucleotides
  • triciribine
  • triciribine phosphate
  • Adenosine Kinase