Combination of α-glucosidase inhibitor and ribavirin for the treatment of dengue virus infection in vitro and in vivo

Jinhong Chang, Wouter Schul, Terry D. Butters, Andy Yip, Boping Liu, Anne Goh, Suresh B. Lakshminarayana, Dominic Alonzi, Gabriele Reinkensmeier, Xiaoben Pan, Xiaowang Qu, Jessica M. Weidner, Lijuan Wang, Wenquan Yu, Nigel Borune, Mark A. Kinch, Jamie E. Rayahin, Robert Moriarty, Xiaodong Xu, Pei Yong ShiJu Tao Guo, Timothy M. Block

Research output: Contribution to journalArticle

60 Scopus citations

Abstract

Cellular α-glucosidases I and II are enzymes that sequentially trim the three terminal glucoses in the N-linked oligosaccharides of viral envelope glycoproteins. This process is essential for the proper folding of viral glycoproteins and subsequent assembly of many enveloped viruses, including dengue virus (DENV). Imino sugars are substrate mimics of α-glucosidases I and II. In this report, we show that two oxygenated alkyl imino sugar derivatives, CM-9-78 and CM-10-18, are potent inhibitors of both α-glucosidases I and II in vitro and in treated animals, and efficiently inhibit DENV infection of cultured human cells. Pharmacokinetic studies reveal that both compounds are well tolerated at doses up to 100. mg/kg in rats and have favorable pharmacokinetic properties and bioavailability in mice. Moreover, we showed that oral administration of either CM-9-78 or CM-10-18 reduces the peak viremia of DENV in mice. Interestingly, while treatment of DENV infected mice with ribavirin alone did not reduce the viremia, combination therapy of ribavirin with sub-effective dose of CM-10-18 demonstrated a significantly enhanced antiviral activity, as indicated by a profound reduction of the viremia. Our findings thus suggest that combination therapy of two broad-spectrum antiviral agents may provide a practically useful approach for the treatment of DENV infection.

Original languageEnglish (US)
Pages (from-to)26-34
Number of pages9
JournalAntiviral research
Volume89
Issue number1
DOIs
StatePublished - Jan 1 2011
Externally publishedYes

Keywords

  • Combination
  • Dengue virus
  • Imino sugar
  • Ribavirin
  • α-Glucosidase

ASJC Scopus subject areas

  • Pharmacology
  • Virology

Fingerprint Dive into the research topics of 'Combination of α-glucosidase inhibitor and ribavirin for the treatment of dengue virus infection in vitro and in vivo'. Together they form a unique fingerprint.

  • Cite this

    Chang, J., Schul, W., Butters, T. D., Yip, A., Liu, B., Goh, A., Lakshminarayana, S. B., Alonzi, D., Reinkensmeier, G., Pan, X., Qu, X., Weidner, J. M., Wang, L., Yu, W., Borune, N., Kinch, M. A., Rayahin, J. E., Moriarty, R., Xu, X., ... Block, T. M. (2011). Combination of α-glucosidase inhibitor and ribavirin for the treatment of dengue virus infection in vitro and in vivo. Antiviral research, 89(1), 26-34. https://doi.org/10.1016/j.antiviral.2010.11.002