Inhibition of Epstein-Barr virus replication by a novel L-nucleoside, 2'-fluoro-5-methyl-beta-L-arabinofuranosyluracil.
A novel L-nucleoside analog, 2'-fluoro-5-methyl-beta-L-arabinofuranosyluracil (L-FMAU), was found to be a potent and selective inhibitor of Epstein-Barr virus (EBV) replication. The decrease in the amount of viral production was concentration dependent with a 90% inhibitory concentration of approximately 5 muM. Upon removal of the drug from treated cells, virus production resumed in 21 days. Metabolism studies indicated that L-FMAU could be converted to its mono-,di- and triphosphate metabolites in both EBV producing and non-producing cells than in EBV non-producing cells. The mechanism of selectivity of L-FMAU against EBV producing cells. However, the amount of L-FMAU nucleotides formed was three times larger in EBV producing cells than in EBV non-producing cells. The mechanism of selectivity of L-FMAU against EBV does not appear to be due solely to the preferential phosphorylation of L-FMAU in EBV producing cells. The triphosphate of L-FMAU could not be utilized as a substrate by EBV DNA polymerase or the human DNA polymerases alpha, beta, gamma, or delta. Therefore, 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 1mM. Given the potent inhibitory activity of this compound against EBV and its inability to be incorporated into cellular DNA, L-FMAU analogs should be explored as a new class of anti-EBV agents.
Yao
G Q
GQ
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510, USA.
Liu
S H
SH
Chou
E
E
Kukhanova
M
M
Chu
C K
CK
Cheng
Y C
YC
D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives* / Q000494:pharmacology; D001345:Autoradiography; D001483:Base Sequence; D002478:Cells, Cultured / Q000187:drug effects; D004247:DNA / Q000187:drug effects*; D004854:Herpesvirus 4, Human / Q000187:drug effects*; D006801:Humans; D008969:Molecular Sequence Data; D014779:Virus Replication / Q000187:drug effects*
D001086:Arabinofuranosyluracil; D004247:DNA; C034935:clevudine