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.
Department of Chemistry and Biomolecular Sciences, University of Ottawa , 10 Marie Curie Private, Ottawa, ON, Canada K1N 6N5.
Matthew A
MA
Lafreniere
Department of Chemistry and Biomolecular Sciences, University of Ottawa , 10 Marie Curie Private, Ottawa, ON, Canada K1N 6N5.
Megan H
MH
Powdrill
Department of Biochemistry, Microbiology, and Immunology, University of Ottawa , 451 Smyth Road, Ottawa, ON, Canada K1H 8M5.
Ragunath
R
Singaravelu
Department of Chemistry and Biomolecular Sciences, University of Ottawa , 10 Marie Curie Private, Ottawa, ON, Canada K1N 6N5.|Department of Biochemistry, Microbiology, and Immunology, University of Ottawa , 451 Smyth Road, Ottawa, ON, Canada K1H 8M5.
John Paul
JP
Pezacki
D000478:Alkylation; D000998:Antiviral Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D006526:Hepatitis C / Q000378:metabolism* / Q000821:virology; D006801:Humans; D018384:Oxidative Stress / Q000187:drug effects*; D016627:Oxidopamine / Q000494:pharmacology*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D014764:Viral Proteins; D016627:Oxidopamine
6-hydroxydopamine; alkylation; antiviral; chemical probe; hepatitis C virus; oxidative stress