Inhibition of dengue virus replication by mycophenolic acid and ribavirin.
Dengue viruses (DEN), mosquito-borne members of the family Flaviviridae, are human pathogens of global significance. The effects of mycophenolic acid (MPA) and ribavirin (RBV) on DEN replication in monkey kidney (LLC-MK2) cells were examined. MPA (IC(50)=0.4+/-0.3 microM) and RBV (IC(50)=50.9+/-18 microM) inhibited DEN2 replication. Quantitative real-time RT-PCR of viral RNA and plaque assays of virions from DEN2-infected and MPA (10 microM)- and RBV (> or =200 microM)-treated cells showed a fivefold increase in defective viral RNA production by cells treated with each drug. Moreover, a dramatic reduction of intracellular viral replicase activity was seen by in vitro replicase assays. Guanosine reversed the inhibition of these compounds, suggesting that one mode of antiviral action of MPA and RBV is by inhibition of inosine monophosphate dehydrogenase and thereby depletion of the intracellular GTP pool. In addition, RBV may act by competing with guanine-nucleotide precursors in viral RNA translation, replication and 5' capping.
Takhampunya
Ratree
R
Department of Microbiology, Faculty of Science, Mahidol University, 272 Rama VI Road, Bangkok 10400, Thailand.|Department of Microbiology and Immunology, Georgetown University School of Medicine, 3900 Reservoir Road, Washington, DC 20057, USA.
Ubol
Sukathida
S
Department of Microbiology, Faculty of Science, Mahidol University, 272 Rama VI Road, Bangkok 10400, Thailand.
Houng
Huo-Shu
HS
Department of Virus Diseases, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
Cameron
Craig E
CE
Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA.
Padmanabhan
Radhakrishnan
R
Department of Microbiology and Immunology, Georgetown University School of Medicine, 3900 Reservoir Road, Washington, DC 20057, USA.
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D003716:Dengue Virus / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology*; D000882:Haplorhini; D006801:Humans; D009173:Mycophenolic Acid / Q000494:pharmacology*; D012367:RNA, Viral / Q000096:biosynthesis / Q000235:genetics; D012324:RNA-Dependent RNA Polymerase / Q000378:metabolism; D012254:Ribavirin / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D012367:RNA, Viral; D012254:Ribavirin; D012324:RNA-Dependent RNA Polymerase; D009173:Mycophenolic Acid