An adenosine nucleoside inhibitor of dengue virus

Zheng Yin, 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 & 14 others 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

Research output: Contribution to journalArticle

203 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)20435-20439
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number48
DOIs
StatePublished - Dec 1 2009
Externally publishedYes

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Dengue Virus
Nucleosides
Adenosine
No-Observed-Adverse-Effect Level
Flavivirus
Flavivirus Infections
Western Equine Encephalitis Viruses
Yellow fever virus
Tick-Borne Encephalitis Viruses
Viruses
RNA Replicase
West Nile virus
Vesicular Stomatitis
Viremia
Viral RNA
Virus Diseases
Therapeutics
Culicidae
Hepacivirus
Antiviral Agents

Keywords

  • Antiviral therapy
  • Flavivirus
  • Viral replication

ASJC Scopus subject areas

  • General

Cite this

An adenosine nucleoside inhibitor of dengue virus. / Yin, Zheng; Chen, Yen Liang; Schul, Wouter; Wang, Qing Yin; Gu, Feng; Duraiswamy, Jeyaraj; Kondreddi, Ravinder Reddy; 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.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 48, 01.12.2009, p. 20435-20439.

Research output: Contribution to journalArticle

Yin, Z, Chen, YL, Schul, W, Wang, QY, Gu, F, Duraiswamy, J, Kondreddi, RR, Niyomrattanakit, P, Lakshminarayana, SB, Goh, A, Xu, HY, Liu, W, Liu, B, Lim, JYH, Ng, CY, Qing, M, Lim, CC, Yip, A, Wang, G, Chan, WL, Tan, HP, Lin, K, Zhang, B, Zou, G, Bernard, KA, Garrett, C, Beltz, K, Dong, M, Weaver, M, He, H, Pichota, A, Dartois, V, Keller, TH & Shi, P-Y 2009, 'An adenosine nucleoside inhibitor of dengue virus', Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 48, pp. 20435-20439. https://doi.org/10.1073/pnas.0907010106
Yin, Zheng ; Chen, Yen Liang ; Schul, Wouter ; Wang, Qing Yin ; Gu, Feng ; Duraiswamy, Jeyaraj ; Kondreddi, Ravinder Reddy ; 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. / An adenosine nucleoside inhibitor of dengue virus. In: Proceedings of the National Academy of Sciences of the United States of America. 2009 ; Vol. 106, No. 48. pp. 20435-20439.
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AU - Duraiswamy, Jeyaraj

AU - Kondreddi, Ravinder Reddy

AU - Niyomrattanakit, Pornwaratt

AU - Lakshminarayana, Suresh B.

AU - Goh, Anne

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AU - Lim, Chin Chin

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AU - Zou, Gang

AU - Bernard, Kristen A.

AU - Garrett, Christine

AU - Beltz, Karen

AU - Dong, Min

AU - Weaver, Margaret

AU - He, Handan

AU - Pichota, Arkadius

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AU - Keller, Thomas H.

AU - Shi, Pei-Yong

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N2 - 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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