Inhibition of encephalomyocarditis virus and poliovirus replication by quinacrine: implications for the design and discovery of novel antiviral drugs.
The 9-aminoacridine (9AA) derivative quinacrine (QC) has a long history of safe human use as an antiprotozoal and antirheumatic agent. QC intercalates into DNA and RNA and can inhibit DNA replication, RNA transcription, and protein synthesis. The extent of QC intercalation into RNA depends on the complexity of its secondary and tertiary structure. Internal ribosome entry sites (IRESs) that are required for initiation of translation of some viral and cellular mRNAs typically have complex structures. Recent work has shown that some intercalating drugs, including QC, are capable of inhibiting hepatitis C virus IRES-mediated translation in a cell-free system. Here, we show that QC suppresses translation directed by the encephalomyocarditis virus (EMCV) and poliovirus IRESs in a cell-free system and in virus-infected HeLa cells. In contrast, IRESs present in the mammalian p53 transcript that are predicted to have less-complex structures were not sensitive to QC. Inhibition of IRES-mediated translation by QC correlated with the affinity of binding between QC and the particular IRES. Expression of viral capsid proteins, replication of viral RNAs, and production of virus were all strongly inhibited by QC (and 9AA). These results suggest that QC and similar intercalating drugs could potentially be used for treatment of viral infections.
Gasparian
Alexander V
AV
Cleveland Biolabs, Inc., Buffalo, New York, USA.
Neznanov
Nickolay
N
Jha
Sujata
S
Galkin
Oleksandr
O
Moran
John J
JJ
Gudkov
Andrei V
AV
Gurova
Katerina V
KV
Komar
Anton A
AA
D000998:Antiviral Agents / Q000494:pharmacology*; D001665:Binding Sites; D004686:Encephalomyocarditis virus / Q000187:drug effects* / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D009690:Nucleic Acid Conformation; D017955:Poliovirus / Q000187:drug effects* / Q000502:physiology; D014176:Protein Biosynthesis / Q000187:drug effects; D011796:Quinacrine / Q000494:pharmacology*; D012367:RNA, Viral / Q000378:metabolism; D014764:Viral Proteins / Q000096:biosynthesis; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D012367:RNA, Viral; D014764:Viral Proteins; D011796:Quinacrine