Journal
ANTIVIRAL RESEARCH
Volume 92, Issue 3, Pages 453-460Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.antiviral.2011.10.002
Keywords
Dengue virus; Celgosivir; alpha-Glucosidase inhibitor; Dengue NS1 protein misfolding; AG129 mouse model for dengue infection
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Funding
- Agency for Science, Technology and Research, Singapore and the Ministry of Health, Singapore
- National Medical Research Council of Singapore
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Dengue virus (DENV) infections continue to spread aggressively around the world. Here we demonstrate that celgosivir (6-O-butanoyl castanospermine), strongly inhibits all four DENV serotypes. We show by fluorescence microscopy that the antiviral mechanism of celgosivir, is in part, due to misfolding and accumulation of DENV non-structural protein 1 (NS1) in the endoplasmic reticulum. Moreover, celgosivir modulates the host's unfolded protein response (UPR) for its antiviral action. Significantly, celgosivir is effective in lethal challenge mouse models that recapitulate primary or secondary antibody-dependent enhanced DENV infection. Celgosivir treated mice showed enhanced survival, reduced viremia and robust immune response, as reflected by serum cytokine analysis. Importantly, survival increased even after treatment was delayed till 2 days post-infection. Together the present study suggests that celgosivir, which has been clinically determined to be safe in humans, may be a valuable candidate for clinical testing in dengue patients. (C) 2011 Elsevier B.M. All rights reserved.
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