title: 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.
authors.affiliation: Department of Microbiology and Immunology, Wake Forest University Medical Center, Winston-Salem, North Carolina 27157.
authors.forename: L S
authors.initials: LS
authors.lastname: Kucera
authors.forename: N P
authors.initials: NP
authors.lastname: Iyer
authors.forename: S H
authors.initials: SH
authors.lastname: Puckett
authors.forename: R W
authors.initials: RW
authors.lastname: Buckheit
authors.forename: L
authors.initials: L
authors.lastname: Westbrook
authors.forename: B R
authors.initials: BR
authors.lastname: Toyer
authors.forename: E L
authors.initials: EL
authors.lastname: White
authors.forename: J M
authors.initials: JM
authors.lastname: Germany-Decker
authors.forename: W M
authors.initials: WM
authors.lastname: Shannon
authors.forename: R C
authors.initials: RC
authors.lastname: Chen
mesh_terms: D000073:Acenaphthenes; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D001569:Benzodiazepines / Q000494:pharmacology; D002460:Cell Line; D016655:HIV Core Protein p24 / Q000187:drug effects; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects*; D015498:HIV-2 / Q000187:drug effects*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015394:Molecular Structure; D012194:RNA-Directed DNA Polymerase / Q000187:drug effects; D018894:Reverse Transcriptase Inhibitors; D012263:Ribonucleosides / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D012265:Ribonucleotides / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000073:Acenaphthenes; D000998:Antiviral Agents; D016655:HIV Core Protein p24; D007093:Imidazoles; D018894:Reverse Transcriptase Inhibitors; D012263:Ribonucleosides; D012265:Ribonucleotides; D001569:Benzodiazepines; C023764:triciribine; C067413:R-82913; C014205:triciribine phosphate; D054303:HIV Reverse Transcriptase; D012194:RNA-Directed DNA Polymerase