Prolonged inhibitory effect of 9-(1,3-dihydroxy-2-propoxymethyl)guanine against replication of Epstein-Barr virus

Abstract

The effects of 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG), a new antiviral drug, and acyclovir (ACV) [9-(2-hydroxyethoxymethyl)guanine] on the replication of Epstein-Barr virus (EBV) were compared. Both drugs inhibited EBV DNA replication in P3HR-1 cells and superinfected Raji cells, but neither inhibited replication of the plasmid form of the EBV genome in latently infected Raji cells. However, DHPG had a more prolonged inhibitory effect than ACV. Although the effect of the drugs is prompt, the kinetics of inhibition of EBV replication indicated that a drug exposure of 14 days was needed to reduce the EBV genome copy number to the residual plasmid level (30 copies per cell). The inhibitory effect of ACV was readily reversed within 11 days after removal of the drug, in contrast to the more prolonged effect exerted by DHPG, which persisted for more than 21 days. The 50% inhibitory doses for cell growth of ACV and DHPG were estimated to be 250 and 200 microM, respectively. The viral 50% and 90% effective doses of inhibition were, respectively, 0.3 and 9 microM for ACV and 0.05 and 3 microM for DHPG. The therapeutic indices (50% inhibitory dose/50% effective dose) for ACV and DHPG were 833 and 4,000, respectively. Synthesis of EBV-associated polypeptides was also affected. In superinfected Raji cells, ACV (100 microM) and DHPG (30 microM) inhibited synthesis of polypeptides with molecular weights of 145,000 and 140,000; in addition, synthesis of polypeptides with molecular weights of 110,000 and 85,000 was markedly reduced by DHPG but not by ACV. However, after drug removal, the inhibitory effect of ACV on polypeptide synthesis was abolished in contrast to the more persistent effect of DHPG.