COMPARATIVE ANTIINFLUENZA 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 mug/ml in primary rhesus monkey kidney and 12 mug/ml in Madin-Darby canine kidney (MDCK) cells, compared to 0.5 mug/ml and 0.9 mug/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 less-than-or-equal-to 0.1 mug/ml in human respiratory epithelial explants, and concentrations up to 100 mug/ml did not inhibit explant outgrowth. Ribavirin was approximately 50-fold less active in this system and inhibited outgrowth at 10 mug/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.