Identification and characterization of inhibitors of West Nile virus.
Although flaviviruses cause significant human diseases, no antiviral therapy is currently available for clinical treatment of these pathogens. To identify flavivirus inhibitors, we performed a high-throughput screening of compound libraries using cells containing luciferase-reporting replicon of West Nile viruses (WNV). Five novel small molecular inhibitors of WNV were identified from libraries containing 96,958 compounds. The inhibitors suppress epidemic strain of WNV in cell culture, with EC(50) (50% effective concentration) values of <10microM and TI (therapeutic index) values of >10. Viral titer reduction assays, using various flaviviruses and nonflaviviruses, showed that the compounds have distinct antiviral spectra. Mode-of-action analysis showed that the inhibitors block distinct steps of WNV replication: four compounds inhibit viral RNA syntheses, while the other compound suppresses both viral translation and RNA syntheses. Biochemical enzyme assays showed that two compounds selectively inhibit viral RNA-dependent RNA polymerase (RdRp), while another compound specifically inhibits both RdRp and methyltransferase. The identified compounds could potentially be developed for treatment of flavivirus infections.
Puig-Basagoiti
Francesc
F
Wadsworth Center, New York State Department of Health, Albany, NY, USA.
Qing
Min
M
Dong
Hongping
H
Zhang
Bo
B
Zou
Gang
G
Yuan
Zhiming
Z
Shi
Pei-Yong
PY
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000633:toxicity; D002522:Chlorocebus aethiops; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D020128:Inhibitory Concentration 50; D008780:Methyltransferases / Q000037:antagonists & inhibitors; D014176:Protein Biosynthesis / Q000187:drug effects; D012367:RNA, Viral / Q000096:biosynthesis; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors; D014158:Transcription, Genetic / Q000187:drug effects; D014709:Vero Cells; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D014902:West Nile virus / Q000187:drug effects*
D000998:Antiviral Agents; D012367:RNA, Viral; D014764:Viral Proteins; D008780:Methyltransferases; D012324:RNA-Dependent RNA Polymerase