Laboratorio de Virología, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires/ IQUIBICEN (CONICET), Ciudad Universitaria, Pabellón 2, Piso 4, Buenos Aires, 1428, Argentina.
Centre National de la Recherche Scientifique (CNRS) and Aix-Marseille Université (AMU), Laboratoire d'Architecture et Fonction des Macromolécules Biologiques (AFMB) UMR 7257, 163 Avenue de Luminy, 13288, Marseille Cedex 9, France.
Antiviral Res. 2020 Apr;176:104749. doi: 10.1016/j.antiviral.2020.104749. Epub 2020 Feb 17.
Flaviviruses constitute a public health concern because of their global burden and the lack of specific antiviral treatment. Here we investigated the antiviral activity of the alkaloid anisomycin against dengue (DENV) and Zika (ZIKV) viruses. At non-cytotoxic concentrations, anisomycin strongly inhibited the replication of reference strains and clinical isolates of all DENV serotypes and Asian and African strains of ZIKV in Vero cells. Anisomycin also prevented DENV and ZIKV multiplication in human cell lines. While initial steps of DENV and ZIKV replicative cycle were unaffected, a high inhibition of viral protein expression was demonstrated after treatment with anisomycin. DENV RNA synthesis was strongly reduced in anisomycin treated cultures, but the compound did not exert a direct inhibitory effect on 2' O-methyltransferase or RNA polymerase activities of DENV NS5 protein. Furthermore, anisomycin-mediated activation of p38 signaling was not related to the antiviral action of the compound. The evaluation of anisomycin efficacy in a mouse model of ZIKV morbidity and mortality revealed that animals treated with a low dose of anisomycin exhibited a significant reduction in viremia levels and died significantly later than the control group. This protective effect was lost at higher doses, though. In conclusion, anisomycin is a potent and selective in vitro inhibitor of DENV and ZIKV that impairs a post-entry step of viral replication; and a low-dose anisomycin treatment may provide some minimal benefit in a mouse model.
黄病毒因其在全球范围内的负担以及缺乏特异性抗病毒治疗而成为公共卫生关注的焦点。在这里，我们研究了生物碱anisomycin 对登革热（DENV）和寨卡（ZIKV）病毒的抗病毒活性。在非细胞毒性浓度下，anisomycin 强烈抑制了所有 DENV 血清型和 ZIKV 的参考株和临床分离株以及亚洲和非洲株在 Vero 细胞中的复制。Anisomycin 还可防止 DENV 和 ZIKV 在人细胞系中的增殖。虽然 DENV 和 ZIKV 复制周期的初始步骤不受影响，但在用 anisomycin 处理后，证明了病毒蛋白表达的高度抑制。在 anisomycin 处理的培养物中，DENV RNA 合成被强烈抑制，但该化合物对 DENV NS5 蛋白的 2'O-甲基转移酶或 RNA 聚合酶活性没有直接抑制作用。此外，anisomycin 介导的 p38 信号转导的激活与该化合物的抗病毒作用无关。在 ZIKV 发病率和死亡率的小鼠模型中评估 anisomycin 的疗效表明，用低剂量 anisomycin 治疗的动物的病毒血症水平显著降低，并且比对照组死亡明显延迟。然而，在更高剂量下，这种保护作用丧失了。总之，anisomycin 是 DENV 和 ZIKV 的一种有效且选择性的体外抑制剂，可损害病毒复制的进入后步骤；并且低剂量 anisomycin 治疗可能在小鼠模型中提供一些最小的益处。
