THE N-7-SUBSTITUTED ACYCLIC NUCLEOSIDE ANALOG 2-AMINO-7-[(1,3-DIHYDROXY-2-PROPOXY)METHYL]PURINE IS A POTENT AND SELECTIVE INHIBITOR OF HERPESVIRUS REPLICATION

2-Amino-7-[(1,3-dihydroxy-2-propoxy)methyl] purine (compound S2242) re presents the first antivirally active nucleoside analog with the side chain attached to the N-7 position of the purine ring. Compound S2242 strongly inhibits the in vitro replication of both herpes simplex viru s type 1 (HSV-1) and type 2 (HSV-2) (50% effective concentration [EC(5 0)], 0.1 to 0.2 mu g/ml), varicella-zoster virus (EC(50), 0.01 to 0.02 mu g/ml) and thymidine kinase (TK)-deficient strains of HSV (EC(50), 0.4 mu g/ml) and varicella-zoster virus (EC(50), 0.2 to 0.5 mu g/ml). Potent activity was also observed against murine cytomegalovirus (EC(5 0), 1 mu g/ml), human cytomegalovirus (HCMV) (EC(50), 0.04 to 0.1 mu g /ml), and human herpesvirus 6 (EC(50), 0.0005 mu g/ml). Compound S2242 (i) was not cytotoxic to confluent Vero, HeLa, or human fibroblast ce lls at concentrations of >100 mu g/ml, (ii) proved somewhat more cytos tatic to Vero, HEL, HeLa, and C1271 cells than ganciclovir, and (iii) was markedly more cytostatic than ganciclovir to the growth of the hum an lymphocytic cell lines HSB-2 and CEM degrees. In contrast to gancic lovir; (i) compound S2242 proved not to be cytocidal to murine mammary carcinoma (FM3A) cells transfected with the HSV-1 or HSV-2 TK gene, ( ii) exogenously added thymidine had only a limited effect on its anti- HSV-1 activity, and (iii) the compound was not phosphorylated by HSV-1 -encoded TK derived from HSV-1 TK-transfected FM3A cells, indicating t hat the compound is not activated by a virally encoded TK. Compound S2 242 inhibited (i) the expression of late HCMV antigens at an EC(50) of 0.07 mu/ml (0.6 mu g/ml for ganciclovir) and (ii) HCMV DNA synthesis at an EC(50) of 0.1 mu g/ml (0.32 mu g/ml for ganciclovir), i.e., valu es that are close to the EC(50)s for inhibition of HCMV-induced cytopa thogenicity. Neither ganciclovir nor S2242 had any effect on the expre ssion of immediate-early HCMV antigens, which occurs before viral DNA synthesis. In time-of-addition experiments, S2242 behaved like gancicl ovir and acyclovir; i.e., the addition of the drugs could be delayed u ntil the onset of viral DNA synthesis.