Selective anabolism of 6-methoxypurine arabinoside in varicella-zoster virus-infected cells.
6-Methoxypurine arabinoside (ara-M) is a highly selective inhibitor of varicella-zoster virus (VZV). It belongs to a class of purine arabinosides whose anti-VZV activity in vitro correlates with substrate utilization by the VZV-encoded thymidine kinase (TK) (D. R. Averett, G. W. Koszalka, J. A. Fyfe, G. B. Roberts, D. J. M. Purifoy, and T. A. Krenitsky, Antimicrob Agents Chemother. 35:851-857, 1991). In this study, the mechanism of action of ara-M was explored. VZV-infected human fibroblasts selectively accumulated ara-M and its phosphorylated metabolites, whereas in uninfected fibroblasts or in those infected with a TK-deficient strain of VZV, there was virtually no cellular uptake of ara-M. The major intracellular metabolite of ara-M in VZV-infected cells was identified as the triphosphate of adenine arabinoside (ara-ATP). Appreciable levels of ara-ADP, ara-AMP, and ara-MMP were also detected. However, di- or triphosphorylated forms of ara-M were not detected. Moreover, in VZV-infected cells, the concentrations of ara-ATP which accumulated in the presence of ara-M were up to eightfold higher than those generated with ara-A itself. In contrast, in uninfected cells, the levels of ara-ATP which accumulated in the presence of ara-M were barely detectable. Clearly, Ara-M activation was dependent on the activity of the virus-encoded TK, while ara-A anabolism resulted primarily from the activity of host cell enzymes. Therefore, ara-M selectively generates the DNA polymerase inhibitor ara-ATP in the VZV-infected cell.
Biron
K K
KK
Wellcome Research Laboratories, Research Triangle Park, North Carolina 27709.
de Miranda
P
P
Burnette
T C
TC
Krenitsky
T A
TA
D001087:Arabinonucleosides / Q000378:metabolism*; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D005347:Fibroblasts / Q000378:metabolism; D006207:Half-Life; D014645:Herpesvirus 3, Human; D006801:Humans; D014740:Vidarabine / Q000378:metabolism; D001084:Vidarabine Phosphate / Q000031:analogs & derivatives / Q000378:metabolism
D001087:Arabinonucleosides; D001084:Vidarabine Phosphate; C000101:ara-ATP; C069956:6-methoxypurine arabinoside; D014740:Vidarabine