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

52 Citations (Scopus)

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 2011
Externally publishedYes

Fingerprint

Glucosidases
Dengue Virus
Ribavirin
Virus Diseases
Imino Sugars
Viremia
Antiviral Agents
Glycoproteins
Pharmacokinetics
Therapeutics
Oligosaccharides
Biological Availability
Oral Administration
Cultured Cells
In Vitro Techniques
Viruses
Glucose
Enzymes
glucosidase I
4-nitrophenyl-alpha-glucosidase

Keywords

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

ASJC Scopus subject areas

  • Virology
  • Pharmacology

Cite this

Combination of α-glucosidase inhibitor and ribavirin for the treatment of dengue virus infection in vitro and in vivo. / Chang, Jinhong; Schul, Wouter; Butters, Terry D.; Yip, Andy; Liu, Boping; Goh, Anne; Lakshminarayana, Suresh B.; Alonzi, Dominic; Reinkensmeier, Gabriele; Pan, Xiaoben; Qu, Xiaowang; Weidner, Jessica M.; Wang, Lijuan; Yu, Wenquan; Borune, Nigel; Kinch, Mark A.; Rayahin, Jamie E.; Moriarty, Robert; Xu, Xiaodong; Shi, Pei-Yong; Guo, Ju Tao; Block, Timothy M.

In: Antiviral Research, Vol. 89, No. 1, 01.2011, p. 26-34.

Research output: Contribution to journalArticle

Chang, J, Schul, W, Butters, TD, Yip, A, Liu, B, Goh, A, Lakshminarayana, SB, Alonzi, D, Reinkensmeier, G, Pan, X, Qu, X, Weidner, JM, Wang, L, Yu, W, Borune, N, Kinch, MA, Rayahin, JE, Moriarty, R, Xu, X, Shi, P-Y, Guo, JT & Block, TM 2011, 'Combination of α-glucosidase inhibitor and ribavirin for the treatment of dengue virus infection in vitro and in vivo', Antiviral Research, vol. 89, no. 1, pp. 26-34. https://doi.org/10.1016/j.antiviral.2010.11.002
Chang, Jinhong ; Schul, Wouter ; Butters, Terry D. ; Yip, Andy ; Liu, Boping ; Goh, Anne ; Lakshminarayana, Suresh B. ; Alonzi, Dominic ; Reinkensmeier, Gabriele ; Pan, Xiaoben ; Qu, Xiaowang ; Weidner, Jessica M. ; Wang, Lijuan ; Yu, Wenquan ; Borune, Nigel ; Kinch, Mark A. ; Rayahin, Jamie E. ; Moriarty, Robert ; Xu, Xiaodong ; Shi, Pei-Yong ; Guo, Ju Tao ; Block, Timothy M. / Combination of α-glucosidase inhibitor and ribavirin for the treatment of dengue virus infection in vitro and in vivo. In: Antiviral Research. 2011 ; Vol. 89, No. 1. pp. 26-34.
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AU - Liu, Boping

AU - Goh, Anne

AU - Lakshminarayana, Suresh B.

AU - Alonzi, Dominic

AU - Reinkensmeier, Gabriele

AU - Pan, Xiaoben

AU - Qu, Xiaowang

AU - Weidner, Jessica M.

AU - Wang, Lijuan

AU - Yu, Wenquan

AU - Borune, Nigel

AU - Kinch, Mark A.

AU - Rayahin, Jamie E.

AU - Moriarty, Robert

AU - Xu, Xiaodong

AU - Shi, Pei-Yong

AU - Guo, Ju Tao

AU - Block, Timothy M.

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