EFFECTS OF ACYCLOVIR, OXETANOCIN-G, AND CARBOCYCLIC OXETANOCIN-G IN COMBINATIONS ON THE REPLICATIONS OF HERPES-SIMPLEX VIRUS TYPE-1 AND TYPE-2 IN VERO CELLS

9-(2-hydroxyethoxymethyl)guanine (acyclovir, ACV) and novel nucleosides, 9-(2-deoxy-2-hydroxymethyl-beta-D-erythro-oxetanocyl)guanine (oxetanocin-G, OXT-G) and (+)-9-[(1R,2R,3S)-2,3-bis(hydroxymethyl)cyclobutyl] guanine (carbocyclic oxetanocin-G, carbocyclic OXT-G) possessed substantial antiviral activities against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2). ACV inhibited only viral thymidine kinase positive (TK+) herpes viruses, although the latter two compounds inhibited the replications of the TK deficient (TK ) mutants of HSV-1 and HSV-2 as well as the TK+ parent strains in vitro. The TK mutants of HSV-1 and HSV-2 (HSV-1 TK and HSV-2 TK were as susceptible to OXT-G as the TK parent strains. However, the TK mutants were less susceptible to carbocyclic OXT-G than the TK+ parent strains. We demonstrated synergistic inhibition of the replications of HSV-1 and HSV-2 by ACV and OXT-G in combination, additive inhibition of HSV-1 and HSV-2 by ACV and carbocyclic OXT-G in combination, synergistic inhibition of HSV-1 by OXT-G and carbocyclic OXT-G in combination, and additive inhibition of HSV-2 by these two compounds. We investigated the metabolism of ACV and OXT-G in HSV-1 TK+-, HSV-1 TK- and mock-infected Vero cells by thin layer chromatography. ACV-triphosphate increased more in HSV-1 TK+-infected Vero cells than in HSV-1 TK-- and mock-infected Vero cells. The metabolism of OXT-G had almost the same pattern in HSV-1 TK+-, HSV-1 TK - and mock-infected Vero cells. These results suggest that ACV is phosphorylated by virus-induced TK, and OXT-G is phosphorylated by cellular nucleoside and nucleotide kinases. oxetanocin-G; carbocyclic oxetanocin-G; ACV; HSV-1 ; HSV-2