Inhibitory effects of novel nucleoside and nucleotide analogues on Epstein-Barr virus replication

The anti-Epstein-Barr virus (EBV) activity of different classes of compounds was assessed by means of an EBV DNA hybridization assay using a digoxigenin-labelled probe specific for the BamHI W fragment of the EBV genome, as well as by measuring viral capsid antigen (VCA) expression after a 7 day incubation period of P3HR-1 producer cells with the test substances. Acyclovir, ganciclovir, cidofovir and zidovudine were included as reference compounds. Several compounds proved to be potent and selective inhibitors of EBV DNA synthesis and VCA expression. Of the new compounds that were evaluated for their anti-EBV activity, the highest efficacy (lowest EC,,) and highest selectivity index ISI) were shown by the purine nucleoside analogue 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine (S2242) (EC50 0.6 ng/ml; SI 600), the acyclic nucleoside phosphonate analogues 9-(2-phosphono-methoxyethyl)-6-dimethylaminopurine (EC50 1.1 mu g/ml; SI 91), 9-(2-phosphonomethoxyethyl)-2-amino-6-benzhydrylaminopurine (EC(50)1.3 mu g/ml; SI 29), 7-(2-phosphonomethoxyethyl)-6-dimethyl-aminopurine (EC50 0.8 mu g/ml; SI 56), 9-(R)-(2-phosphonomethoxypropyl)-6-(2-dimethylaminoethylaminopurine (EC50 0.5 mu g/ml; SI 42), the 2',3'-dideoxythymidine derivative 3'-oximino-2',3'-dideoxythymidine (EC50 1.5 mu g/ml; SI 65), and 1-(2,3-dideoxy-3-N-hydroxyamino-beta-D-threo-pentafuranyl)pentafuranosyl)thymine (EC50 4.1 mu g/ml; SI >24).