Journal
ANTIVIRAL RESEARCH
Volume 92, Issue 2, Pages 329-340Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.antiviral.2011.09.001
Keywords
2 '-Deoxy-2 '-fluorocytidine; Fluorodeoxyribonucleosides; H5N1 avian influenza virus; BALB/c mouse; Pandemic H1N1 virus
Categories
Funding
- Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health
- Southern Research Institute [N01-AI-30063]
- Virology Branch, National Institute of Allergy and Infectious Diseases
- Department of Health and Human Services [N01-AI-30048]
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Various fluorodeoxyribonucleosides were evaluated for their antiviral activities against influenza virus infections in vitro and in vivo. Among the most potent inhibitors was 2'-deoxy-2'-fluorocytidine (2'-FdC). It inhibited various strains of low and highly pathogenic avian influenza H5N1 viruses, pandemic H1N1 viruses, an oseltamivir-resistant pandemic H1N1 virus, and seasonal influenza viruses (H3N2, H1N1, influenza B) in MDCK cells, with the 90% inhibitory concentrations ranging from 0.13 to 4.61 mu M, as determined by a virus yield reduction assay. 2'-FdC was then tested for efficacy in BALB/c mice infected with a lethal dose of highly pathogenic influenza A/Vietnam/1203/2004 H5N1 virus. 2'FdC (60 mg/kg/d) administered intraperitoneally (i.p.) twice a day beginning 24 h after virus exposure significantly promoted survival (80% survival) of infected mice (p = 0.0001). Equally efficacious were the treatment regimens in which mice were treated with 2'-FdC at 30 or 60 mg/kg/day (bid X 8) beginning 24 h before virus exposure. At these doses, 70-80% of the mice were protected from death due to virus infection (p = 0.0005, p = 0.0001; respectively). The lungs harvested from treated mice at day four of the infection displayed little surface pathology or histopathology, lung weights were lower, and the 60 mg/kg dose reduced lung virus titers, although not significantly compared to the placebo controls. All doses were well tolerated in uninfected mice. 2'-FdC could also be administered as late as 72 h post virus exposure and still significantly protect 60% mice from the lethal effects of the H5N1 virus infection (p = 0.019). Other fluorodeoxyribonucleosides tested in the H5N1 mouse model, 2'-deoxy-5-fluorocytidine and 2'-deoxy-2',2'-difluorocytidine, were very toxic at higher doses and not inhibitory at lower doses. Finally, 2'-FdC, which was active in the H5N1 mouse model, was also active in a pandemic H1N1 influenza A infection model in mice. When given at 30 mg/kg/d (bid X 5) beginning 24 h before virus exposure), 2'-FdC also significantly enhanced survival of H1N1-infected mice (50%, p = 0.038) similar to the results obtained in the H5N1 infection model using a similar dosing regimen (50%, p < 0.05). Given the demonstrated in vitro and in vivo inhibition of avian influenza virus replication, 2'-FdC may qualify as a lead compound for the development of agents treating influenza virus infections. (C) 2011 Elsevier B.V. All rights reserved.
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