Grupo de Transdução de Sinal/Flavivírus, Department of Microbiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
Laboratório de Vírus, Department of Microbiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
Arch Virol. 2021 May;166(5):1433-1438. doi: 10.1007/s00705-021-05021-1. Epub 2021 Mar 8.
The recent introduction of Zika virus (ZIKV), the recurrence of dengue virus (DENV), and the lethality of yellow fever virus (YFV) have had a significant impact on Brazilian society and public health. Here, we targeted two cellular kinases implicated in cell proliferation and cancer that are also important for viral replication: mitogen-activated protein kinase kinase (MEK) and Src. We used two MEK inhibitors - trametinib and selumetinib - and two Src inhibitors - saracatinib and bosutinib - to inhibit ZIKV, DENV, and YFV replication in cell culture. The cytotoxicity of the four inhibitors was determined by the observation of abnormal morphology and quantification of adherent cells by crystal violet staining. The antiviral activity of these drugs was assessed based on the reduction of plaque-forming units in cell culture as evidence of the inhibition of the replication of the selected flaviviruses. All four inhibitors showed antiviral activity, but among them, trametinib was the safest and most efficacious against all of the viruses, inhibiting the replication of ZIKV and YFV by 1000-fold, and DENV2/3 by nearly 100-fold. This pan-antiviral effect shows that trametinib could be repurposed for the treatment of flaviviral infections.
寨卡病毒（ZIKV）、登革热病毒（DENV）的再次出现以及黄热病毒（YFV）的致死性对巴西社会和公共卫生造成了重大影响。在这里，我们针对两种与细胞增殖和癌症有关的细胞激酶进行了研究，这两种激酶对病毒复制也很重要：丝裂原活化蛋白激酶激酶（MEK）和Src。我们使用了两种 MEK 抑制剂——曲美替尼和塞尔美替尼，以及两种 Src 抑制剂——沙卡替尼和博舒替尼，来抑制细胞培养中的 ZIKV、DENV 和 YFV 复制。通过观察异常形态和结晶紫染色定量贴壁细胞来确定四种抑制剂的细胞毒性。根据细胞培养中噬菌斑形成单位的减少来评估这些药物的抗病毒活性，这证明了所选黄病毒复制的抑制。这四种抑制剂都表现出抗病毒活性，但其中，曲美替尼对所有病毒的安全性和有效性最高，对 ZIKV 和 YFV 的抑制作用达到了 1000 倍，对 DENV2/3 的抑制作用接近 100 倍。这种广谱抗病毒作用表明，曲美替尼可被重新用于治疗黄病毒感染。
