Inhibition of influenza virus transcription by 2'-deoxy-2'-fluoroguanosine.

Antimicrobial Agents and Chemotherapy
M TisdaleM Ford

Abstract

The nucleoside analog 2'-deoxy-2'-fluoroguanosine (2'-fluorodGuo) is phosphorylated by cellular enzymes and reversibly inhibits influenza virus replication in chick embryo cells within the first 4 h of infection. RNA hybridization studies revealed that primary and secondary transcription of influenza virus RNA were blocked at a compound concentration of 10 microM, but no inhibition of cell protein synthesis was seen even at high compound concentrations (200 microM). In vitro, the triphosphate of 2'-fluorodGuo is a competitive inhibitor of influenza virus transcriptase activity from disrupted virus, with a Ki of 1.0 microM. The cellular polymerases DNA polymerase alpha and RNA polymerase II were only weakly inhibited or were insusceptible to 2'-fluorodGTP. In kinetic studies with the influenza virus transcriptase, 2'-fluorodGTP, in the absence of GTP, blocked elongation of the virus RNA chain. Similarly, by using purified ribonucleoprotein complexes it was found that the addition of a single nucleotide of 2'-fluorodGTP to the virus RNA caused chain termination, which resulted in the blockage of further virus transcription. Furthermore, the specificity for influenza virus transcriptase was confirmed when the transcriptase from pa...Continue Reading

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Dec 2, 2006·Nature Reviews. Drug Discovery·Erik De Clercq
Jul 5, 2005·Expert Opinion on Investigational Drugs·C Cianci, M Krystal
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Feb 29, 2000·The Journal of Biological Chemistry·K KlumppB Handa
Jun 27, 2007·Organic Letters·Adib CharafeddinePeter Strazewski

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