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Antimicrobial Agents and Chemotherapy, June 2008, p. 2097-2110, Vol. 52, No. 6
0066-4804/08/$08.00+0     doi:10.1128/AAC.01227-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Inhibition of Hepatitis C Virus (HCV) RNA Polymerase by DNA Aptamers: Mechanism of Inhibition of In Vitro RNA Synthesis and Effect on HCV-Infected Cells{triangledown} ,{dagger}

Pantxika Bellecave,1,3 Christian Cazenave,1,3 Julie Rumi,1,3 Cathy Staedel,2,3 Ophélie Cosnefroy,1,3 Marie-Line Andreola,1,3 Michel Ventura,1,3 Laura Tarrago-Litvak,1,3 and Thérèse Astier-Gin1,3*

CNRS UMR 5234,1 INSERM U869,2 Université Victor Segalen Bordeaux 2, 146, rue Léo Saignat, 33076 Bordeaux Cedex, France3

Received 18 September 2007/ Returned for modification 9 November 2007/ Accepted 7 March 2008

We describe here the further characterization of two DNA aptamers that specifically bind to hepatitis C virus (HCV) RNA polymerase (NS5B) and inhibit its polymerase activity in vitro. Although they were obtained from the same selection procedure and contain an 11-nucleotide consensus sequence, our results indicate that aptamers 27v and 127v use different mechanisms to inhibit HCV polymerase. While aptamer 27v was able to compete with the RNA template for binding to the enzyme and blocked both the initiation and the elongation of RNA synthesis, aptamer 127v competed poorly and exclusively inhibited initiation and postinitiation events. These results illustrate the power of the selective evolution of ligands by exponential enrichment in vitro selection procedure approach to select specific short DNA aptamers able to inhibit HCV NS5B by different mechanisms. We also determined that, in addition to an in vitro inhibitory effect on RNA synthesis, aptamer 27v was able to interfere with the multiplication of HCV JFH1 in Huh7 cells. The efficient cellular entry of these short DNAs and the inhibitory effect observed on human cells infected with HCV indicate that aptamers are useful tools for the study of HCV RNA synthesis, and their use should become a very attractive and alternative approach to therapy for HCV infection.

* Corresponding author. Mailing address: CNRS UMR5234, Université Victor Segalen Bordeaux 2, 146, rue Léo Saignat, Bordeaux 33076 Cedex, France. Phone: 33 5 57 57 17 42. Fax: 33 5 57 57 17 66. E-mail: therese.astier{at}reger.u-bordeaux2.fr

{triangledown} Published ahead of print on 27 March 2008.

{dagger} Supplemental material for this article may be found at http://aac.asm.org/.

Antimicrobial Agents and Chemotherapy, June 2008, p. 2097-2110, Vol. 52, No. 6
0066-4804/08/$08.00+0     doi:10.1128/AAC.01227-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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