6-Hydroxydopamine Inhibits the Hepatitis C Virus through Alkylation of Host and Viral Proteins and the Induction of Oxidative Stress.
Many viruses, including the hepatitis C virus (HCV), are dependent on the host RNA silencing pathway for replication. In this study, we screened small molecule probes, previously reported to disrupt loading of the RNA-induced silencing complex (RISC), including 6-hydroxydopamine (6-OHDA), suramin (SUR), and aurintricarboxylic acid (ATA), to examine their effects on viral replication. We found that 6-OHDA inhibited HCV replication; however, 6-OHDA was a less potent inhibitor of RISC than either SUR or ATA. By generating a novel chemical probe (6-OHDA-yne), we determined that 6-OHDA covalently modifies host and virus proteins. Moreover, 6-OHDA was shown to be an alkylating agent that is capable of generating adducts with a number of enzymes involved in the oxidative stress response. Furthermore, modification of viral enzymes with 6-OHDA and 6-OHDA-yne was found to inhibit their enzymatic activity. Our findings suggest that 6-OHDA is a probe for oxidative stress as well as protein alkylation, and these properties together contribute to the antiviral effects of this compound.
['Lafreniere|Matthew A|MA|', 'Powdrill|Megan H|MH|', 'Singaravelu|Ragunath|R|', 'Pezacki|John Paul|JP|']
D000478:Alkylation D000998:Antiviral Agents D045744:Cell Line, Tumor D049109:Cell Proliferation D016174:Hepacivirus D006526:Hepatitis C D006801:Humans D018384:Oxidative Stress D016627:Oxidopamine D014764:Viral Proteins D014779:Virus Replication
6-hydroxydopamine hepatitis C virus alkylation oxidative stress chemical probe antiviral