Campos Guilherme Rodrigues Fernandes, Bittar Cíntia, Jardim Ana Carolina Gomes, Shimizu Jacqueline Farinha, Batista Mariana Nogueira, Paganini Eder Ramos, Assis Letícia Ribeiro de, Bartlett Christopher, Harris Mark, Bolzani Vanderlan da Silva, Regasini Luis Octavio, Rahal Paula
Institute of Bioscience, Language and Exact Science, IBILCE, UNESP - São Paulo State University, São José do Rio Preto, SP, Brazil.
Institute of Biomedical Science, ICBIM, UFU - Federal University of Uberlândia, Uberlândia, MG, Brazil.
J Gen Virol. 2017 Jul;98(7):1693-1701. doi: 10.1099/jgv.0.000808. Epub 2017 Jul 12.
Hepatitis C virus (HCV) affects about 170 million people worldwide. The current treatment has a high cost and variable response rates according to the virus genotype. Acridones, a group of compounds extracted from natural sources, showed potential antiviral actions against HCV. Thus, this study aimed to evaluate the effect of a panel of 14 synthetic acridones on the HCV life cycle. The compounds were screened using an Huh7.5 cell line stably harbouring the HCV genotype 2a subgenomic replicon SGR-Feo-JFH-1. Cells were incubated in the presence or absence of compounds for 72 h and cell viability and replication levels were assessed by MTT and luciferase assays, respectively. At a concentration of 5 µM the acridone Fac4 exhibited a >90 % inhibition of HCV replication with no effect on cell viability. The effects of Fac4 on virus replication, entry and release steps were evaluated in Huh7.5 cells infected with the JFH-1 isolate of HCV (HCVcc). Fac4 inhibited JFH-1 replication to approximately 70 %, while no effect was observed on virus entry. The antiviral activity of Fac4 was also observed on viral release, with almost 80 % of inhibition. No inhibitory effect was observed against genotype 3 replication. Fac4 was able to intercalate into dsRNA, however did not inhibit NS5B polymerase activity or translation driven by the HCV IRES. Although its mode of action is partly understood, Fac4 presents significant inhibition of HCV replication and can therefore be considered as a candidate for the development of a future anti-HCV treatment.
丙型肝炎病毒（HCV）在全球约影响1.7亿人。目前的治疗成本高昂，且根据病毒基因型的不同，反应率也有所差异。吖啶酮是一类从天然来源提取的化合物，对HCV显示出潜在的抗病毒作用。因此，本研究旨在评估一组14种合成吖啶酮对HCV生命周期的影响。使用稳定携带HCV基因型2a亚基因组复制子SGR-Feo-JFH-1的Huh7.5细胞系对这些化合物进行筛选。细胞在有或无化合物存在的情况下孵育72小时，分别通过MTT和荧光素酶测定评估细胞活力和复制水平。在浓度为5µM时，吖啶酮Fac4对HCV复制的抑制率>90%，且对细胞活力无影响。在感染HCV JFH-1分离株（HCVcc）的Huh7.5细胞中评估了Fac4对病毒复制、进入和释放步骤的影响。Fac4将JFH-1复制抑制至约70%，而对病毒进入未观察到影响。在病毒释放方面也观察到了Fac4的抗病毒活性，抑制率近80%。未观察到对基因型3复制的抑制作用。Fac4能够插入双链RNA，但不抑制NS5B聚合酶活性或由HCV IRES驱动的翻译。尽管其作用方式部分已知，但Fac4对HCV复制有显著抑制作用，因此可被视为未来抗HCV治疗药物开发的候选药物。
