Hepatitis C virus in vitro replication is efficiently inhibited by acridone Fac4

Made available in DSpace on 2018-12-11T17:33:26Z (GMT). No. of bitstreams: 0 Previous issue date: 2017-07-01 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG) 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. Institute of Bioscience Language and Exact Science IBILCE UNESP –São Paulo State University Institute of Biomedical Science ICBIM UFU –Federal University of Uberlândia School of Molecular and Cellular Biology Faculty of Biological Sciences Astbury Centre for Structural Molecular Biology University of Leeds Institute of Chemistry São Paulo State University Institute of Bioscience Language and Exact Science IBILCE UNESP –São Paulo State University Institute of Chemistry São Paulo State University CNPq: 165802/2015-4 FAPESP: 2012/01403-9 FAPESP: 2014/22198-0 CNPq: 445021/2014-4 FAPEMIG: APQ-00587-14 CNPq: SICONV 793988/2013