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| Content Provider | PubMed Central |
|---|---|
| Author | Yin, Zheng Chen, Yen-liang Schul, Wouter Wang, Qing-yin Gu, Feng Duraiswamy, Jeyaraj Reddy, Kondreddi Ravinder Niyomrattanakit, Pornwaratt Lakshminarayana, Suresh B. Goh, Anne Xu, Hao Ying Liu, Wei Liu, Boping Lim, Joanne Y. H. Ng, Chuan Young Qing, Min Lim, Chin Chin Yip, Andy Wang, Gang Chan, Wai Ling Tan, Hui Pen Lin, Kai Zhang, Bo Zou, Gang Bernard, Kristen A. Garrett, Christine Beltz, Karen Dong, Min Weaver, Margaret He, Handan Pichota, Arkadius Dartois, Veronique Keller, Thomas H. Shi, Pei-yong |
| Abstract | Dengue virus (DENV), a mosquito-borne flavivirus, is a major public health threat. The virus poses risk to 2.5 billion people worldwide and causes 50 to 100 million human infections each year. Neither a vaccine nor an antiviral therapy is currently available for prevention and treatment of DENV infection. Here, we report a previously undescribed adenosine analog, NITD008, that potently inhibits DENV both in vitro and in vivo. In addition to the 4 serotypes of DENV, NITD008 inhibits other flaviviruses, including West Nile virus, yellow fever virus, and Powassan virus. The compound also suppresses hepatitis C virus, but it does not inhibit nonflaviviruses, such as Western equine encephalitis virus and vesicular stomatitis virus. A triphosphate form of NITD008 directly inhibits the RNA-dependent RNA polymerase activity of DENV, indicating that the compound functions as a chain terminator during viral RNA synthesis. NITD008 has good in vivo pharmacokinetic properties and is biologically available through oral administration. Treatment of DENV-infected mice with NITD008 suppressed peak viremia, reduced cytokine elevation, and completely prevented the infected mice from death. No observed adverse effect level (NOAEL) was achieved when rats were orally dosed with NITD008 at 50 mg/kg daily for 1 week. However, NOAEL could not be accomplished when rats and dogs were dosed daily for 2 weeks. Nevertheless, our results have proved the concept that a nucleoside inhibitor could be developed for potential treatment of flavivirus infections. |
| Related Links | http://dx.doi.org/10.1073/pnas.0907010106 |
| Ending Page | 20439 |
| Page Count | 5 |
| Starting Page | 20435 |
| File Format | |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 48 |
| Volume Number | 106 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2009-12-01 |
| Access Restriction | Open |
| Rights Holder | National Academy of Sciences |
| Subject Keyword | General Research in Higher Education |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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