This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Flint, M.
Right arrow Articles by Howe, A. Y. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Flint, M.
Right arrow Articles by Howe, A. Y. M.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, February 2009, p. 401-411, Vol. 53, No. 2
0066-4804/09/$08.00+0     doi:10.1128/AAC.01081-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Selection and Characterization of Hepatitis C Virus Replicons Dually Resistant to the Polymerase and Protease Inhibitors HCV-796 and Boceprevir (SCH 503034) {triangledown}

Mike Flint,1* Stanley Mullen,1 Anne M. Deatly,1 Wei Chen,1 Lynn Z. Miller,1 Robert Ralston,2 Colin Broom,3 Emilio A. Emini,1 and Anita Y. M. Howe1,{dagger}

Wyeth Research, 401 North Middletown Road, Pearl River, New York 10965,1 Schering-Plough, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033,2 ViroPharma Inc., 397 Eagleview Boulevard, Exton, Pennsylvania 193413

Received 11 August 2008/ Returned for modification 26 September 2008/ Accepted 10 October 2008

HCV-796 is a nonnucleoside inhibitor of the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) polymerase, and boceprevir is an inhibitor of the NS3 serine protease. The emergence of replicon variants resistant to the combination of HCV-796 and boceprevir was evaluated. Combining the inhibitors greatly reduced the frequency with which resistant colonies arose; however, some resistant replicon cells could be isolated by the use of low inhibitor concentrations. These replicons were approximately 1,000-fold less susceptible to HCV-796 and 9-fold less susceptible to boceprevir. They also exhibited resistance to anthranilate nonnucleoside inhibitors of NS5B but were fully sensitive to inhibitors of different mechanisms: a pyranoindole, Hsp90 inhibitors, an NS5B nucleoside inhibitor, and pegylated interferon (Peg-IFN). The replicon was cleared from the combination-resistant cells by extended treatment with Peg-IFN. Mutations known to confer resistance to HCV-796 (NS5B C316Y) and boceprevir (NS3 V170A) were present in the combination-resistant replicons. These changes could be selected together and coexist in the same genome. The replicon bearing both changes exhibited reduced sensitivity to inhibition by HCV-796 and boceprevir but had a reduced replicative capacity.

* Corresponding author. Mailing address: Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965. Phone: (845) 602-5168. Fax: (845) 474-3242. E-mail: flintm{at}wyeth.com

{triangledown} Published ahead of print on 20 October 2008.

{dagger} Present address: Tibotec, Generaal De Wittelaan, L11, B3, Mechelen 2800, Belgium.

Antimicrobial Agents and Chemotherapy, February 2009, p. 401-411, Vol. 53, No. 2
0066-4804/09/$08.00+0     doi:10.1128/AAC.01081-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»