SAIJO, M., SUZUTANI, T. and YOSHIDA, I.
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. Tohoku J. Exp. Med., 1992,
167 (1), 57-68-9-(2-hydroxyethoxymethyl)guanine (acyclovir, ACV) and novel nucleosides, 9-(2-deoxy-2-hydroxymethyl-β-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.
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