Activity of Triciribine and Triciribine-5′ -Monophosphate Against Human Immunodeficiency Virus Types 1 and 2

Abstract

Triciribine (TCN) and its 5'-monophosphate (TCN-P) are novel tricyclic compounds with known antitumor activity; TCN-P is currently in phase II human clinical trials. We now report that these compounds have potent and selective activity against HIV-1 and HIV-2. Using a syncytial plaque assay, TCN and TCN-P were active against HIV-1 at 0.01-0.02 microM and had differential selectivities of 2250 and 1900, respectively, compared to 1850 for AZT. In contrast, TCN and TCN-P had minimal selectivity against human cytomegalovirus (50 and 27, respectively). TCN and TCN-P markedly inhibited HIV-1-induced p24 core antigen production, reverse transcriptase, and infectious virus production in a dose-dependent manner using HIV-1 acutely infected CEM-SS, H9, and persistently infected H9IIIB and U1 cells. In acutely infected PBL cells, TCN and TCN-P inhibited reverse transcriptase and infectious virus production but not p24 core antigen production. Using a microtiter XTT assay, TCN and TCN-P were active against a panel of HIV-1 and HIV-2 strains at IC50 values ranging from 0.02 to 0.46 microM. Evaluation of matched pairs of predrug and postdrug therapy HIV-1 isolates established that AZT-resistant and TIBO-resistant variants of HIV-1 were sensitive to TCN or TCN-P. Furthermore, unlike AZT and other fraudulent nucleosides, neither TCN, TCN-P, nor TCN-TP inhibited the viral reverse transcriptase. Thus, even though triciribine is a nucleoside chemically, it does not act biologically by classic nucleoside modalities but rather by a unique mechanism yet to be elucidated.

Metabolism, Biochemical Actions, and Chemical Synthesis of Anticancer Nucleosides, Nucleotides, and Base Analogs

“…In 1971, Schram and Townsend synthesized triciribine 30 , a tricyclic derivative of a purine nucleoside as a potential anticancer drug, which has also been studied as an antiretroviral agent against HIV-1 and HIV-2 . Triciribine 30 , however, is poorly soluble, and this suboptimal property led to the development of the highly soluble prodrug triciribine-5′-monophosphate 33 .…”

Acyclic Sugar Analogs of Triciribine: Lack of Antiviral and Antiproliferative Activity Correlate with Low Intracellular Phosphorylation

“…33 These studies also found no cross resistance to TCN or TCN-P in AZT-or TIBO-resistant HIV strains.33 Similar to its antiproliferative activity in L1210 cells, TCN must be phosphorylated to TCN-P to be active against HIV. 34 Together with the data on the lack of cross resistance, the results suggest that TCN and TCN-P have an entirely different mode of action than AZT or TIBO.…”

“…Furthermore, cytotoxicity such as that observed in murine L1210 cells appears to be highly cell line specific3 and was not observed in human cell lines used to propagate HIV and human cytomegalovirus (HCMV). 33 Studies on the antiviral mechanism of action of TCN are currently underway.…”

Akt‐independent effects of triciribine on ACE2 expression in human lung epithelial cells: Potential benefits in restricting SARS‐CoV2 infection

“…TCBN is a tricyclic adenosine analog that is phosphorylated to its active metabolite (TCBN‐P) by adenosine kinase in certain cells, such as the lung epithelial cells (Wotring et al, 1986). TCBN can inhibit viral replication of HIV‐1 and HIV‐2 independent of Akt, including strains known to be resistant to azidothymidine or TIBO (Kucera et al, 1993). The phosphorylation of TCBN to TCBN‐P has been reported to be essential for its antiviral activity on HIV‐1 (Porcari et al, 2003; Ptak et al, 2010).…”