Phosphorylation of triciribine is necessary for activity against HIV type 1.

Important note: Information in this article was accurate in 1999. The state of the art may have changed since the publication date.

Phosphorylation of triciribine is necessary for activity against HIV type 1.

AIDS Res Hum Retroviruses. 1998 Oct 10;14(15):1315-22. Unique Identifier : AIDSLINE MED/99002721
Ptak RG; Borysko KZ; Porcari AR; Buthod JL; Holland LE; Shipman C Jr; Townsend LB; Drach JC; Department of Biologic and Materials Sciences, School of; Dentistry, University of Michigan, Ann Arbor 48109-1078, USA.

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.

Keywords: JOURNAL ARTICLE Adenosine Kinase/ANTAGONISTS & INHIB/METABOLISM Anti-HIV Agents/*PHARMACOLOGY/PHARMACOKINETICS Biotransformation Enzyme Inhibitors/PHARMACOLOGY Human HIV-1/*DRUG EFFECTS Jurkat Cells Phosphorylation Ribonucleosides/CHEMISTRY/*PHARMACOLOGY/PHARMACOKINETICS Ribonucleotides/CHEMISTRY/*PHARMACOLOGY/PHARMACOKINETICS Support, U.S. Gov't, P.H.S. Tumor Cells, Cultured
990228
A9920899

AEGiS is a 501(c)3, not-for-profit, tax-exempt, educational corporation. AEGiS is made possible through unrestricted funding from Boehringer Ingelheim, Bridgestone/Firestone Charitable Trust, Bristol-Myers Squibb Company, Elton John AIDS Foundation, Gill Foundation, the National Library of Medicine, Quest Diagnostics, Roche and Trimeris, and donations from users like you. Always watch for outdated information. This article first appeared in 1999. This material is designed to support, not replace, the relationship that exists between you and your doctor.

AEGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.

Copyright ©1980, 1999. AEGiS. All materials appearing on AEGiS are protected by copyright as a collective work or compilation under U.S. copyright and other laws and are the property of AEGiS, or the party credited as the provider of the content. .