Inhibition of RNA recruitment and replication of an RNA virus by acridine derivatives with known anti-prion activities.
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.


RESULTS
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.


CONCLUSIONS
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 viruses.
Sasvari
Zsuzsanna
Z
Department of Plant Pathology, University of Kentucky, Lexington, Kentucky, United States of America.
Bach
Stéphane
S
Blondel
Marc
M
Nagy
Peter D
PD
D000166:Acridines / Q000737:chemistry*; D000998:Antiviral Agents / Q000494:pharmacology; D002626:Chemistry, Pharmaceutical / Q000379:methods; D002746:Chlorpromazine / Q000494:pharmacology; D015195:Drug Design; D008957:Models, Genetic; D010942:Plant Viruses / Q000378:metabolism; D017096:Prion Diseases / Q000188:drug therapy*; D011328:Prions / Q000235:genetics*; D011796:Quinacrine / Q000494:pharmacology; D012313:RNA / Q000737:chemistry*; D012328:RNA Viruses / Q000235:genetics*; D017864:Tombusvirus / Q000235:genetics; D014764:Viral Proteins / Q000378:metabolism; D014779:Virus Replication
D000166:Acridines; D000998:Antiviral Agents; D011328:Prions; D014764:Viral Proteins; D012313:RNA; D011796:Quinacrine; D002746:Chlorpromazine