A translation inhibitor that suppresses dengue virus in vitro and in vivo

Qing Yin Wang, Ravinder Reddy Kondreddi, Xuping Xie, Ranga Rao, Shahul Nilar, Hao Ying Xu, Min Qing, David Chang, Hongping Dong, Fumiaki Yokokawa, Suresh B. Lakshminarayana, Anne Goh, Wouter Schul, Laura Kramer, Thomas H. Keller, Pei Yong Shi

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

We describe a novel translation inhibitor that has anti-dengue virus (DENV) activity in vitro and in vivo. The inhibitor was identified through a high-throughput screening using a DENV infection assay. The compound contains a benzomorphan core structure. Mode-of-action analysis indicated that the compound inhibits protein translation in a viral RNA sequence-independent manner. Analysis of the stereochemistry demonstrated that only one enantiomer of the racemic compound inhibits viral RNA translation. Medicinal chemistry was performed to eliminate a metabolically labile glucuronidation site of the compound to improve its in vivo stability. Pharmacokinetic analysis showed that upon a single subcutaneous dosing of 25 mg/kg of body weight in mice, plasma levels of the compound reached a Cmax (maximum plasma drug concentration) above the protein-binding-adjusted 90% effective concentration (EC90) value of 0.96 μM. In agreement with the in vivo pharmacokinetic results, treatment of DENV-infected mice with 25 mg/kg of compound once per day reduced peak viremia by about 40-fold. However, mice treated with 75 mg/kg of compound per day exhibited adverse effects. Collectively, our results demonstrate that the benzomorphan compounds inhibit DENV through suppression of RNA translation. The therapeutic window of the current compounds needs to be improved for further development.

Original languageEnglish (US)
Pages (from-to)4072-4080
Number of pages9
JournalAntimicrobial agents and chemotherapy
Volume55
Issue number9
DOIs
StatePublished - Sep 1 2011

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ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Wang, Q. Y., Kondreddi, R. R., Xie, X., Rao, R., Nilar, S., Xu, H. Y., Qing, M., Chang, D., Dong, H., Yokokawa, F., Lakshminarayana, S. B., Goh, A., Schul, W., Kramer, L., Keller, T. H., & Shi, P. Y. (2011). A translation inhibitor that suppresses dengue virus in vitro and in vivo. Antimicrobial agents and chemotherapy, 55(9), 4072-4080. https://doi.org/10.1128/AAC.00620-11