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.
Saijo
M
M
Departments of Pediatrics, Asahikawa Medical College, Japan.
Suzutani
T
T
Yoshida
I
I
D000212:Acyclovir / Q000494:pharmacology*; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004347:Drug Interactions; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015394:Molecular Structure; D009154:Mutation; D010766:Phosphorylation; D018139:Simplexvirus / Q000187:drug effects* / Q000235:genetics; D013936:Thymidine / Q000378:metabolism; D014709:Vero Cells; D010948:Viral Plaque Assay; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; C057479:oxetanocin G; D006147:Guanine; D013936:Thymidine; D000212:Acyclovir