Comparison of Foscarnet and Foscarnet Esters as Anti-Influenza Virus Agents

Abstract

Foscarnet is shown to inhibit influenza A virus replication by inhibiting viral RNA synthesis in infected cells. Viral RNA synthesis by isolated nuclei from infected cells was as sensitive to foscarnet as viral RNA synthesis by enzymes from isolated virions or viral cores. It is, therefore, unlikely that the mere association of the polymerase in a replication complex, as in isolated nuclei and infected cells, is the reason for the fact that foscarnet is 10-20 times less active in inhibiting virus replication than cell-free RNA synthesis. We, therefore, tested 44 esters of foscarnet for improved antiviral effect. Of these only a few phenyl esters were more potent than foscarnet itself. These esters did not inhibit the viral RNA polymerase activity and may be hydrolyzed intracellularly to foscarnet. The increased antiviral potency of the phenyl esters was, however, accompanied by increased cellular toxicity, and these compounds, therefore, were less selective antiviral agents than foscarnet. The results suggest that it is not possible to increase the anti-influenza activity of foscarnet by converting it to an ester.