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Antimicrobial Agents and Chemotherapy, September 2009, p. 3715-3719, Vol. 53, No. 9
0066-4804/09/$08.00+0 doi:10.1128/AAC.00392-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Anti-Human Immunodeficiency Virus Activity, Cross-Resistance, Cytotoxicity, and Intracellular Pharmacology of the 3'-Azido-2',3'-Dideoxypurine Nucleosides
Nicolas Sluis-Cremer,1*
Dianna Koontz,1
Leda Bassit,2
Brenda I. Hernandez-Santiago,2
Mervi Detorio,2
Kim L. Rapp,2
Franck Amblard,2
Lavanya Bondada,2
Jason Grier,2
Steven J. Coats,3
Raymond F. Schinazi,2 and
John W. Mellors1
Department of Medicine, Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261,1 Center for AIDS Research, Department of Pediatrics, Emory University School of Medicine, and Veterans Affairs Medical Center, Decatur, Georgia 30033,2 RFS Pharma, LLC, Tucker, Georgia 300843
Received 24 March 2009/ Returned for modification 21 April 2009/ Accepted 1 July 2009
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 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 (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.
* Corresponding author. Mailing address: Department of Medicine, Division of Infectious Diseases, University of Pittsburgh School of Medicine, S817 Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261. Phone: (412) 648-8457. Fax: (412) 648-8521. E-mail: nps2{at}pitt.edu
Published ahead of print on 13 July 2009.
Antimicrobial Agents and Chemotherapy, September 2009, p. 3715-3719, Vol. 53, No. 9
0066-4804/09/$08.00+0 doi:10.1128/AAC.00392-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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