The absence of any formally licensed antiadenovirus drugs and the increasing incidence of life-threatening
adenovirus infections in immunosuppressed patients warrant the development of effective antiadenovirus compounds. A detailed study was performed on the antiadenovirus activities of several classes of
nucleoside and
nucleotide analogues in human embryonic lung fibroblast cells. The antiadenovirus activities were evaluated by three methods, viz., evaluating the adenoviral cytopathic effect, monitoring cell viability by a colorimetric assay, and real-time PCR quantitation of
viral DNA as a direct parameter for virus replication. The most active and selective compounds were the acyclic
nucleoside phosphonate analogues
cidofovir, its
adenine analogue (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine [(
S)-HPMPA], and the new derivative (S)-2,4-diamino-6-[3-hydroxy-2-(phosphonomethoxy)propoxy]
pyrimidine [(S)-HPMPO-DAPy]; the N7-substituted acyclic derivative 2-amino-7-(1,3-dihydroxy-2-propoxymethyl)purine (
S-2242); and the 2',3'-dideoxynucleoside analogues
zalcitabine and
alovudine. No antiadenovirus activity was observed for the
antiviral drugs ribavirin,
foscarnet,
acyclovir,
penciclovir, and
brivudin, while
ganciclovir displayed modest activity. However, in human
osteosarcoma cells transfected with herpes simplex virus
thymidine kinase,
ganciclovir demonstrated highly potent antiadenovirus activity, suggesting that the efficacy of
ganciclovir against adenovirus is limited by inefficient phosphorylation in adenovirus-infected cells, rather than by insufficient inhibition at the
viral DNA polymerase level. Collectively, our
antiviral data show that the adenovirus
DNA polymerase exhibits sensitivity to a relatively broad spectrum of inhibitors and should be studied further as an
antiviral target in antiadenovirus drug development programs.