title: Anti-human immunodeficiency virus activity, cross-resistance, cytotoxicity, and intracellular pharmacology of the 3'-azido-2',3'-dideoxypurine nucleosides.
abstract: Although the approved nucleoside reverse transcriptase (RT) inhibitors (NRTI) are integral components of therapy for human immunodeficiency virus type 1 (HIV-1) infection, they can have significant limitations, including the selection of NRTI-resistant HIV-1 and cellular toxicity. Accordingly, there is a critical need to develop new NRTI that have excellent activity and safety profiles and exhibit little or no cross-resistance with existing drugs. In this study, we report that the 3'-azido-2',3'-dideoxypurine nucleosides (ADPNs) 3'-azido-2',3'-dideoxyadenosine (3'-azido-ddA) and 3'-azido-2',3'-dideoxyguanosine (3'-azido-ddG) exert potent antiviral activity in primary human lymphocytes and HeLa and T-cell lines (50% inhibitory concentrations [IC50s] range from 0.19 to 2.1 microM for 3'-azido-ddG and from 0.36 to 10 microM for 3'-azido-ddA) and that their triphosphate forms are incorporated as efficiently as the natural dGTP or dATP substrates by HIV-1 RT. Importantly, both 3'-azido-ddA and 3'-azido-ddG retain activity against viruses containing K65R, L74V, or M184V (IC50 change of <2.0-fold) and against those containing three or more thymidine analog mutations (IC50 change of <3.5-fold). In addition, 3'-azido-ddG does not exhibit cytotoxicity in primary lymphocytes or epithelial or T-cell lines and does not decrease the mitochondrial DNA content of HepG2 cells. Furthermore, 3'-azido-ddG is efficiently phosphorylated to 3'-azido-ddGTP in human lymphocytes, with an intracellular half-life of the nucleoside triphosphate of 9 h. The present data suggest that additional preclinical studies are warranted to assess the potential of ADPNs for treatment of HIV-1 infection.
authors: Department of Medicine, Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. nps2@pitt.edu
authors: Nicolas
authors: N
authors: Sluis-Cremer
authors: Dianna
authors: D
authors: Koontz
authors: Leda
authors: L
authors: Bassit
authors: Brenda I
authors: BI
authors: Hernandez-Santiago
authors: Mervi
authors: M
authors: Detorio
authors: Kim L
authors: KL
authors: Rapp
authors: Franck
authors: F
authors: Amblard
authors: Lavanya
authors: L
authors: Bondada
authors: Jason
authors: J
authors: Grier
authors: Steven J
authors: SJ
authors: Coats
authors: Raymond F
authors: RF
authors: Schinazi
authors: John W
authors: JW
authors: Mellors
mesh_terms: D019380:Anti-HIV Agents / Q000009:adverse effects* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D015224:Dideoxynucleosides / Q000009:adverse effects* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D015658:HIV Infections / Q000188:drug therapy; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D015394:Molecular Structure; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D015224:Dideoxynucleosides; D018894:Reverse Transcriptase Inhibitors; C051073:3'-azido-2',3'-dideoxyguanosine