Identification of active antiviral compounds against a New York isolate of West Nile virus.
The recent West Nile virus (WNV) outbreak in the United States has increased the need to identify effective therapies for this disease. A chemotherapeutic approach may be a reasonable strategy because the virus infection is typically not chronic and antiviral drugs have been identified to be effective in vitro against other flaviviruses. A panel of 34 substances was tested against infection of a recent New York isolate of WNV in Vero cells and active compounds were also evaluated in MA-104 cells. Some of these compounds were also evaluated in Vero cells against the 1937 Uganda isolate of the WNV. Six compounds were identified to be effective against virus-induced CPE with 50% effective concentrations (EC50) less than 10 microg/ml and with a selectivity index (SI) of greater than 10. Known inhibitors of orotidine monophosphate decarboxylase and inosine monophosphate dehydrogenase involved in the synthesis of GTP, UTP, and TTP were most effective. The compounds 6-azauridine, 6-azauridine triacetate, cyclopententylcytosine (CPE-C), mycophenolic acid and pyrazofurin appeared to have the greatest activities against the New York isolate, followed by 2-thio-6-azauridine. Anti-WNV activity of 6-azauridine was confirmed by virus yield reduction assay when the assay was performed 2 days after initial infection in Vero cells. The neutral red assay mean EC50 of ribavirin was only 106 microg/ml with a mean SI of 9.4 against the New York isolate and only slightly more effective against the Uganda isolate. There were some differences in the drug sensitivities of the New York and Uganda isolates, but when comparisons were made by categorizing drugs according to their modes of action, similarities of activities between the two isolates were identified.
Morrey
John D
JD
Department of Animal, Dairy, and Veterinary Sciences, Institute for Antiviral Research, Utah State University, Logan, UT 84322-4700, USA. jmorrey@cc.usu.edu
Smee
Donald F
DF
Sidwell
Robert W
RW
Tseng
Christopher
C
D000577:Amides; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001380:Azauridine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002522:Chlorocebus aethiops; D003562:Cytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D009173:Mycophenolic Acid / Q000494:pharmacology; D009518:New York; D011720:Pyrazoles; D012254:Ribavirin / Q000494:pharmacology; D012263:Ribonucleosides / Q000494:pharmacology; D012266:Ribose; D013891:Thiouridine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014709:Vero Cells; D014779:Virus Replication / Q000187:drug effects; D014902:West Nile virus / Q000187:drug effects* / Q000302:isolation & purification / Q000502:physiology
D000577:Amides; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D012263:Ribonucleosides; D013891:Thiouridine; C009456:2-thio-6-azauridine; D012254:Ribavirin; C002997:pyrazofurin; D003562:Cytidine; D012266:Ribose; C045911:cyclopentenyl cytosine; D001380:Azauridine; D009173:Mycophenolic Acid; C100231:azaribine