Comparative anti-influenza virus activity of 2'-deoxy-2'-fluororibosides in vitro.
The anti-influenza virus activity of 2'-deoxy-2'-fluoroguanosine was determined in cell culture and in explants of human respiratory epithelium by yield reduction assay. The concentration causing at least 1.0 log10 reduction in influenza A (H3N2) virus yield (EC90) at 24 h was 2.5 micrograms/ml in primary rhesus monkey kidney and 12 micrograms/ml in Madin-Darby canine kidney (MDCK) cells, compared to 0.5 micrograms/ml and 0.9 micrograms/ml, respectively, for ribavirin. The estimated therapeutic ratios for both compounds were low (< 5 to 25) in these cell types. In contrast, the EC90 values at 48 h for influenza A and influenza B virus were < or = 0.1 micrograms/ml in human respiratory epithelial explants, and concentrations up to 100 micrograms/ml did not inhibit explant outgrowth. Ribavirin was approximately 50-fold less active in this system and inhibited outgrowth at 10 micrograms/ml. 2'-deoxy-2'-fluoroguanosine was also approx. 45-fold more potent than the corresponding adenosine and inosine compounds in explant cultures. Partially resistant variants, with approximate 5-fold increases in EC50 values, could be selected by serial influenza A virus passage in MDCK cells in the presence of 2'-deoxy-2'-fluoroguanosine, which indicated that its antiviral activity is at least partially virus specific. The exceptional activity of 2'-deoxy-2'-fluoroguanosine in human respiratory epithelial cells against both influenza A and B viruses makes this compound an interesting candidate for further investigation.
Rollins
B S
BS
Department of Internal Medicine, University of Virginia Health Sciences Center, Charlottesville 22908.
Elkhatieb
A H
AH
Hayden
F G
FG
D000234:Adenoids / Q000187:drug effects / Q000382:microbiology; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004285:Dogs; D004848:Epithelium / Q000187:drug effects / Q000382:microbiology; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects / Q000254:growth & development; D007668:Kidney / Q000187:drug effects / Q000382:microbiology; D008253:Macaca mulatta; D009297:Nasal Mucosa / Q000187:drug effects / Q000382:microbiology
D000998:Antiviral Agents; C083670:2'-deoxy-2'-fluoroguanosine; D003849:Deoxyguanosine