6-Methoxypurine arabinoside as a selective and potent inhibitor of varicella-zoster virus.
Seven 6-alkoxypurine arabinosides were synthesized and evaluated for in vitro activity against varicella-zoster virus (VZV). The simplest of the series, 6-methoxypurine arabinoside (ara-M), was the most potent, with 50% inhibitory concentrations ranging from 0.5 to 3 microM against eight strains of VZV. This activity was selective. The ability of ara-M to inhibit the growth of a variety of human cell lines was at least 30-fold less (50% effective concentration, greater than 100 microM) than its ability to inhibit the virus. Enzyme studies suggested the molecular basis for these results. Of the seven 6-alkoxypurine arabinosides, ara-M was the most efficient substrate for VZV-encoded thymidine kinase as well as the most potent antiviral agent. In contrast, it was not detectably phosphorylated by any of the three major mammalian nucleoside kinases. Upon direct comparison, ara-M was appreciably more potent against VZV than either acyclovir or adenine arabinoside (ara-A). However, in the presence of an adenosine deaminase inhibitor, the arabinosides of adenine and 6-methoxypurine were equipotent but not equally selective; the adenine congener had a much less favorable in vitro chemotherapeutic index. Again, this result correlated with data from enzyme studies in that ara-A, unlike ara-M, was a substrate for two mammalian nucleoside kinases. Unlike acyclovir and ara-A, ara-M had no appreciable activity against other viruses of the herpes group. The potency and selectivity of ara-M as an anti-VZV agent in vitro justify its further study.
Averett
D R
DR
Wellcome Research Laboratories, Research Triangle Park, North Carolina 27709.
Koszalka
G W
GW
Fyfe
J A
JA
Roberts
G B
GB
Purifoy
D J
DJ
Krenitsky
T A
TA
D000212:Acyclovir / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology*; D001087:Arabinonucleosides / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D014645:Herpesvirus 3, Human / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D007700:Kinetics; D013937:Thymidine Kinase / Q000378:metabolism; D014740:Vidarabine / Q000494:pharmacology
D000998:Antiviral Agents; D001087:Arabinonucleosides; C008099:hypoxanthine arabinoside; C069956:6-methoxypurine arabinoside; D013937:Thymidine Kinase; D014740:Vidarabine; D000212:Acyclovir