Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore, Singapore.
Antiviral Res. 2011 Dec;92(3):453-60. doi: 10.1016/j.antiviral.2011.10.002. Epub 2011 Oct 12.
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.
登革热病毒（DENV）在全球范围内继续迅速传播。在这里，我们证明了 celgosivir（6-O-丁酰基苦棟子胺）强烈抑制所有四种 DENV 血清型。我们通过荧光显微镜观察到，celgosivir 的抗病毒机制部分是由于 DENV 非结构蛋白 1（NS1）在内质网中的错误折叠和积累。此外，celgosivir 调节宿主未折叠蛋白反应（UPR）以发挥其抗病毒作用。重要的是，celgosivir 在模拟原发性或继发性抗体依赖性增强 DENV 感染的致死性挑战小鼠模型中有效。用 celgosivir 治疗的小鼠表现出更高的存活率、更低的病毒血症和更强的免疫反应，这反映在血清细胞因子分析中。重要的是，即使在感染后 2 天开始治疗也会延迟，存活率仍会增加。综上所述，已在临床上确定对人类安全的 celgosivir 可能是登革热患者临床测试的有价值候选药物。
