INHIBITION OF EPSTEIN-BARR-VIRUS REPLICATION BY A NOVEL E,2'-FLUORO-5-METHYL-BETA-L-ARABINOFURANOSYLURACIL

A novel L-nucleoside analog, 2'-fluoro-5-methyl-beta-L-arabinofuranosy luracil (L-FMAU), was found to be a potent and selective inhibitor of Epstein-Barr virus (EBV) replication. The decrease in the amount of vi ral production was concentration dependent with a 90% inhibitory conce ntration of approximately 5 mu M. Upon removal of the drug from treate d cells, virus production resumed in 21 days. Metabolism studies indic ated that L-FMAU could be converted to its mono-, di- and triphosphate metabolites in both EBV producing and non-producing cells. However, t he amount of L-FMAU nucleotides formed was three times larger in EBV p roducing cells than in EBV non-producing cells. The mechanism of selec tivity of L-FMAU against EBV does not appear to be due solely to the p referential phosphorylation of L-FMAU in ERV producing cells. The trip hosphate of L-FMAU could not be utilized as a substrate by EBV DNA pol ymerase or the human DNA polymerases alpha, beta, gamma, or delta. The refore, the incorporation of L-FMAU residues into viral DNA may not be the mechanism of antiviral activity. This compound appears to have a mechanism of action different from that of any other antiherpes virus nucleoside analogs. In addition, L-FMAU has very low cytotoxicity with 50% inhibition of cell growth occurring at a concentration of 1 mM. G iven the potent inhibitory activity of this compound against EBV and i ts inability to be incorporated into cellular DNA, L-FMAU analogs shou ld be explored as a new class of anti-EBV agents.