Phosphorylation of triciribine is necessary for activity against HIV type 1

RG PTAK, KZ BORYSKO, AR PORCARI… - AIDS research and …, 1998 - liebertpub.com
RG PTAK, KZ BORYSKO, AR PORCARI, JL BUTHOD, LE HOLLAND, C SHIPMAN JR…
AIDS research and human retroviruses, 1998liebertpub.com
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 μM gave intracellular TCN-P concentrations …
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 μM gave intracellular TCN-P concentrations from 27 to 775 μM, 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.
Mary Ann Liebert