Unique inhibitory effect of 1-(2'-deoxy-2'-fluoro-beta-L-arabinofuranosyl)-5-methyluracil 5'-triphosphate on Epstein-Barr virus and human DNA polymerases.
Biochem Pharmacol
; 55(8): 1181-7, 1998 Apr 15.
Article
en En
| MEDLINE
| ID: mdl-9719472
ABSTRACT
1-(2'-Deoxy-2'-fluoro-beta-L-arabinofuranosyl)-5-methyluracil (L-FMAU) was shown to have potent antiviral activity against Epstein-Barr virus (EBV) without any cellular toxicity at concentrations up to 200 microM (Yao et al., Biochem Pharmacol 51 941-947, 1996). The 5'-triphosphate of L-FMAU was not a substrate for EBV or cellular DNA polymerases, but could inhibit the elongation reaction, 3'-to-5' exonuclease activity, and nucleotide turnover catalyzed by EBV DNA polymerase. DNA synthesis catalyzed by human DNA polymerases was inhibited to a lesser extent. The inhibition pattern of EBV DNA polymerase by L-FMAU-5'-triphosphate (L-FMAU-TP) was consistent with an uncompetitive mechanism when dNTP or template-primer were used as the variable substrates. The Ki values were 38+/-10 microM for the elongation reaction, and about 50+/-10 microM for both nucleotide exchange and 3'-to-5' exonuclease reactions, values that were 10-20 times less than that for GMP. L-FMAU-TP is the first nucleoside 5'-triphosphate shown to have such unique behavior toward DNA polymerases. EBV DNA polymerase could be one of the targets for the inhibitory effect of L-FMAU-TP on EBV replication.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Antivirales
/
Trifosfato de Arabinofuranosil Citosina
/
Proteínas Virales
/
Herpesvirus Humano 4
/
Inhibidores de la Síntesis del Ácido Nucleico
/
Proteínas de Unión al ADN
Límite:
Humans
Idioma:
En
Revista:
Biochem Pharmacol
Año:
1998
Tipo del documento:
Article
País de afiliación:
Estados Unidos