Inhibition of RNA Recruitment and Replication of an RNA Virus by Acridine Derivatives with Known Anti-Prion Activities
Open Access
- 13 October 2009
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 4 (10), e7376
- https://doi.org/10.1371/journal.pone.0007376
Abstract
BACKGROUND: Small molecule inhibitors of RNA virus replication are potent antiviral drugs and useful to dissect selected steps in the replication process. To identify antiviral compounds against Tomato bushy stunt virus (TBSV), a model positive stranded RNA virus, we tested acridine derivatives, such as chlorpromazine (CPZ) and quinacrine (QC), which are active against prion-based diseases. METHODOLOGY/PRINCIPAL FINDINGS: Here, we report that CPZ and QC compounds inhibited TBSV RNA accumulation in plants and in protoplasts. In vitro assays revealed that the inhibitory effects of these compounds were manifested at different steps of TBSV replication. QC was shown to have an effect on multiple steps, including: (i) inhibition of the selective binding of the p33 replication protein to the viral RNA template, which is required for recruitment of viral RNA for replication; (ii) reduction of minus-strand synthesis by the tombusvirus replicase; and (iii) inhibition of translation of the uncapped TBSV genomic RNA. In contrast, CPZ was shown to inhibit the in vitro assembly of the TBSV replicase, likely due to binding of CPZ to intracellular membranes, which are important for RNA virus replication. CONCLUSION/SIGNIFICANCE: Since we found that CPZ was also an effective inhibitor of other plant viruses, including Tobacco mosaic virus and Turnip crinkle virus, it seems likely that CPZ has a broad range of antiviral activity. Thus, these inhibitors constitute effective tools to study similarities in replication strategies of various RNA virusesThis publication has 73 references indexed in Scilit:
- A Key Role for Heat Shock Protein 70 in the Localization and Insertion of Tombusvirus Replication Proteins to Intracellular MembranesJournal of Virology, 2009
- Translation elongation factor 1A is a component of the tombusvirus replicase complex and affects the stability of the p33 replication co-factorVirology, 2009
- In vitro assembly of the Tomato bushy stunt virus replicase requires the host Heat shock protein 70Proceedings of the National Academy of Sciences of the United States of America, 2008
- Mouse Hepatitis Virus Type 2 Enters Cells through a Clathrin-Mediated Endocytic Pathway Independent of Eps15Journal of Virology, 2008
- A γ-secretase inhibitor and quinacrine reduce prions and prevent dendritic degeneration in murine brainsProceedings of the National Academy of Sciences of the United States of America, 2008
- Cdc34p Ubiquitin-Conjugating Enzyme Is a Component of the Tombusvirus Replicase Complex and Ubiquitinates p33 Replication ProteinJournal of Virology, 2008
- Authentic Replication and Recombination of Tomato Bushy Stunt Virus RNA in a Cell-Free Extract from YeastJournal of Virology, 2008
- Lethal Mutagenesis of Picornaviruses with N-6-Modified Purine Nucleoside AnaloguesAntimicrobial Agents and Chemotherapy, 2008
- Clathrin-Dependent Entry of Severe Acute Respiratory Syndrome Coronavirus into Target Cells Expressing ACE2 with the Cytoplasmic Tail DeletedJournal of Virology, 2007
- Identification of Essential Host Factors Affecting Tombusvirus RNA Replication Based on the Yeast Tet Promoters Hughes CollectionJournal of Virology, 2006