Inhibition of dengue virus RNA synthesis by an adenosine nucleoside

Yen Liang Chen, Zheng Yin, Jeyaraj Duraiswamy, Wouter Schul, Chin Chin Lim, Boping Liu, Hao Ying Xu, Min Qing, Andy Yip, Gang Wang, Wai Ling Chan, Hui Pen Tan, Melissa Lo, Sarah Liung, Ravinder Reddy Kondreddi, Ranga Rao, Helen Gu, Handan He, Thomas H. Keller, Pei Yong Shi

Research output: Contribution to journalArticle

51 Scopus citations

Abstract

We recently reported that (2R,3R,4R,5R)-2-(4-amino-pyrrolo[2,3-d]pyrimidin- 7-yl)-3-ethynyl-5-hydroxymethyl-tetrahydro-furan-3,4-diol is a potent inhibitor of dengue virus (DENV), with 50% effective concentration (EC50) and cytotoxic concentration (CC50) values of 0.7 μM and >100 μM, respectively. Here we describe the synthesis, structure-activity relationship, and antiviral characterization of the inhibitor. In an AG129 mouse model, a single-dose treatment of DENV-infected mice with the compound suppressed peak viremia and completely prevented death. Mode-of-action analysis using a DENV replicon indicated that the compound blocks viral RNA synthesis. Recombinant adenosine kinase could convert the compound to a monophosphate form. Suppression of host adenosine kinase, using a specific inhibitor (iodotubercidin) or small interfering RNA (siRNA), abolished or reduced the compound's antiviral activity in cell culture. Studies of rats showed that 14C-labeled compound was converted to mono-, di-, and triphosphate metabolites in vivo. Collectively, the results suggest that this adenosine inhibitor is phosphorylated to an active (triphosphate) form which functions as a chain terminator for viral RNA synthesis.

Original languageEnglish (US)
Pages (from-to)2932-2939
Number of pages8
JournalAntimicrobial agents and chemotherapy
Volume54
Issue number7
DOIs
StatePublished - Jul 2010

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ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Chen, Y. L., Yin, Z., Duraiswamy, J., Schul, W., Lim, C. C., Liu, B., Xu, H. Y., Qing, M., Yip, A., Wang, G., Chan, W. L., Tan, H. P., Lo, M., Liung, S., Kondreddi, R. R., Rao, R., Gu, H., He, H., Keller, T. H., & Shi, P. Y. (2010). Inhibition of dengue virus RNA synthesis by an adenosine nucleoside. Antimicrobial agents and chemotherapy, 54(7), 2932-2939. https://doi.org/10.1128/AAC.00140-10