In:
Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 53, No. 9 ( 2009-09), p. 3715-3719
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 [IC 50 s] range from 0.19 to 2.1 μM for 3′-azido-ddG and from 0.36 to 10 μM 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 (IC 50 change of 〈 2.0-fold) and against those containing three or more thymidine analog mutations (IC 50 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.
Type of Medium:
Online Resource
ISSN:
0066-4804
,
1098-6596
DOI:
10.1128/AAC.00392-09
Language:
English
Publisher:
American Society for Microbiology
Publication Date:
2009
detail.hit.zdb_id:
1496156-8
SSG:
12
SSG:
15,3
