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.
Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore, Singapore.
Abhay P S
AP
Rathore
Prasad N
PN
Paradkar
Satoru
S
Watanabe
Kah Hin
KH
Tan
Cynthia
C
Sung
John E
JE
Connolly
Jenny
J
Low
Eng Eong
EE
Ooi
Subhash G
SG
Vasudevan
D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D006224:Cricetinae; D003715:Dengue / Q000188:drug therapy* / Q000235:genetics; D003716:Dengue Virus / Q000187:drug effects*; D004195:Disease Models, Animal; D006801:Humans; D007212:Indolizines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D057507:Mice, 129 Strain; D008826:Microbial Sensitivity Tests; D011485:Protein Binding; D017510:Protein Folding / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D056811:Unfolded Protein Response / Q000187:drug effects / Q000235:genetics; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000378:metabolism*; D054836:Indolizidines
D000998:Antiviral Agents; D007212:Indolizines; D017361:Viral Nonstructural Proteins; C070715:celgosivir; D054836:Indolizidines