Celgosivir treatment misfolds dengue virus NS1 protein, induces cellular pro-survival genes and protects against lethal challenge mouse model

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.

► Celgosivir is an effective nanomolar concentration inhibitor against all four dengue virus serotypes. ► Celgosivir effectively inhibits DENV-2 in ADE infected THP-1 cells. ► NS1 protein misfolds and accumulates in the ER during celgosivir treatment. ► Celgosivir treatment promotes the induction of pro-survival ER stress response genes. ► Celgosivir treatment is effective upto 48 h post-virus infection in a lethal challenge mouse model.