2. Academic Validation
  3. An adenosine nucleoside inhibitor of dengue virus

An adenosine nucleoside inhibitor of dengue virus

  • Proc Natl Acad Sci U S A. 2009 Dec 1;106(48):20435-9. doi: 10.1073/pnas.0907010106.
Zheng Yin 1,  Yen-Liang Chen,  Wouter Schul,  Qing-Yin Wang,  Feng Gu,  Jeyaraj Duraiswamy,  Ravinder Reddy Kondreddi,  Pornwaratt Niyomrattanakit,  Suresh B Lakshminarayana,  Anne Goh,  Hao Ying Xu,  Wei Liu,  Boping Liu,  Joanne Y H Lim,  Chuan Young Ng,  Min Qing,  Chin Chin Lim,  Andy Yip,  Gang Wang,  Wai Ling Chan,  Hui Pen Tan,  Kai Lin,  Bo Zhang,  Gang Zou,  Kristen A Bernard,  Christine Garrett,  Karen Beltz,  Min Dong,  Margaret Weaver,  Handan He,  Arkadius Pichota,  Veronique Dartois,  Thomas H Keller,  Pei-Yong Shi
Affiliations

Affiliation

  • 1 Novartis Institute for Tropical Diseases, Singapore, 138670, Singapore.
PMID: 19918064 DOI: 10.1073/pnas.0907010106
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.

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