Inhibition of adenovirus DNA polymerase by modified nucleoside triphosphate analogs correlate with their antiviral effects on cellular level

Adenovirus (Ad) infection results in significant morbidity and mortality in both immunocompetent and immunosuppressed hosts. There is currently no lic ensed chemotherapy effective in dealing with this virus infection. In this study the anti-adenoviral activity of a group of modified nucleoside analog s was investigated. The most efficient 3-fluorosubstituted nucleoside triph osphate inhibitors of Ad DNA polymerase were 3'-fluorothymidine triphosphat e (IC50 0.63 muM), 2',3'-dideoxy-3'-fluoroguanosine triphosphate (IC50 0.71 muM) and 2',3'-dideoxy-3'-fluorouridine triphosphate (IC50 2.96 muM). The most efficient 2',3'-dideoxynucleoside triphosphates were 2',3'-dideoxycyti dine triphosphate (ddCTP; IC50 1.0 muM), 2',3'-dideoxyadenosine triphosphat e (IC50 1.6 muM) and 2',3'-dideoxythymidine triphosphate (IC50 1.82 muM) Ki netic studies indicate competitive inhibition of adenovirus DNA polymerase by ddCTP. These data confirm results previously obtained at the cellular le vel using a focus reduction assay involving Ad2-infected FL cells. Whereas the D-enantiomers 3'-fluorothymidine and 2',3'-dideoxycytidine are potent i nhibitors of adenoviral replication, the corresponding L-enantiomers exhibi ted no inhibitory activity.