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ACS Infect Dis. 2016 Nov 11;2(11):863-871. Epub 2016 Oct 13.

6-Hydroxydopamine Inhibits the Hepatitis C Virus through Alkylation of Host and Viral Proteins and the Induction of Oxidative Stress.

Author information

1
Department of Chemistry and Biomolecular Sciences, University of Ottawa , 10 Marie Curie Private, Ottawa, ON, Canada K1N 6N5.
2
Department of Biochemistry, Microbiology, and Immunology, University of Ottawa , 451 Smyth Road, Ottawa, ON, Canada K1H 8M5.

Abstract

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.

KEYWORDS:

6-hydroxydopamine; alkylation; antiviral; chemical probe; hepatitis C virus; oxidative stress

PMID:
27682680
DOI:
10.1021/acsinfecdis.6b00098
[Indexed for MEDLINE]

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