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 licensed chemotherapy effective in dealing with this virus infection. In this study the anti-adenoviral activity of a group of modified nucleoside analogs was investigated. The most efficient 3-fluorosubstituted nucleoside triphosphate inhibitors of Ad DNA polymerase were 3'-fluorothymidine triphosphate (IC50 0.63 microM), 2',3'-dideoxy-3'-fluoroguanosine triphosphate (IC50 0.71 microM) and 2',3'-dideoxy-3'-fluorouridine triphosphate (IC50 2.96 microM). The most efficient 2',3'-dideoxynucleoside triphosphates were 2',3'-dideoxycytidine triphosphate (ddCTP; IC50 1.0 microM), 2',3'-dideoxyadenosine triphosphate (IC50 1.6 microM) and 2',3'-dideoxythymidine triphosphate (IC50 1.82 microM). Kinetic studies indicate competitive inhibition of adenovirus DNA polymerase by ddCTP. These data confirm results previously obtained at the cellular level using a focus reduction assay involving Ad2-infected FL cells. Whereas the D-enantiomers 3'-fluorothymidine and 2',3'-dideoxycytidine are potent inhibitors of adenoviral replication, the corresponding L-enantiomers exhibited no inhibitory activity.
Mentel
R
R
Friedrich-Loeffler-Institut für Medizinische Mikrobiologie, Ernst Mortiz-Arndt-Universität Greifswald, Germany.
Kurek
S
S
Wegner
U
U
Janta-Lipinski
M
M
Gürtler
L
L
Matthes
E
E
D000260:Adenoviruses, Human / Q000187:drug effects* / Q000201:enzymology*; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D003845:Deoxycytosine Nucleotides / Q000378:metabolism / Q000494:pharmacology; D054306:Dideoxynucleotides; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D019384:Nucleic Acid Synthesis Inhibitors; D009711:Nucleotides / Q000494:pharmacology*; D013237:Stereoisomerism
D000998:Antiviral Agents; D003845:Deoxycytosine Nucleotides; D054306:Dideoxynucleotides; D004791:Enzyme Inhibitors; D019384:Nucleic Acid Synthesis Inhibitors; D009711:Nucleotides; C037406:2',3'-dideoxycytidine 5'-triphosphate; D004259:DNA-Directed DNA Polymerase