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Antimicrobial Agents and Chemotherapy, May 2006, p. 1813-1822, Vol. 50, No. 5
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.5.1813-1822.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

VX-950, a Novel Hepatitis C Virus (HCV) NS3-4A Protease Inhibitor, Exhibits Potent Antiviral Activities in HCV Replicon Cells

Kai Lin, Robert B. Perni, Ann D. Kwong, and Chao Lin*

Vertex Pharmaceuticals Incorporated, 130 Waverly Street, Cambridge, MA 02139

Received 24 October 2005/ Returned for modification 9 January 2006/ Accepted 7 March 2006

The NS3-4A serine protease of hepatitis C virus (HCV) is essential for viral replication and therefore has been one of the most attractive targets for developing specific antiviral agents against HCV. VX-950, a highly selective, reversible, and potent peptidomimetic inhibitor of the HCV NS3-4A protease, is currently in clinical development for the treatment of hepatitis C. In this report, we describe the in vitro characterization of anti-HCV activities of VX-950 in subgenomic HCV replicon cells. Incubation with VX-950 resulted in a time- and dose-dependent reduction of HCV RNA and proteins in replicon cells. Moreover, following a 2-week incubation with VX-950, a reduction in HCV RNA levels of 4.7 log10 was observed, and this reduction resulted in elimination of HCV RNA from replicon cells, since there was no rebound in replicon RNA after withdrawal of the inhibitor. The combination of VX-950 and alpha interferon was additive to moderately synergistic in reducing HCV RNA in replicon cells with no significant increase in cytotoxicity. The benefit of the combination was sustained over time: a 4-log10 reduction in HCV RNA level was achieved following a 9-day incubation with VX-950 and alpha interferon at lower concentrations than when either VX-950 or alpha interferon was used alone. The combination of VX-950 and alpha interferon also suppressed the emergence of in vitro resistance mutations against VX-950 in replicon cells.

* Corresponding author. Mailing address: Vertex Pharmaceuticals Incorporated, 130 Waverly Street, Cambridge, MA 02139. Phone: (617) 444-6202. Fax: (617) 444-6210. E-mail: chao_lin{at}vrtx.com.

Antimicrobial Agents and Chemotherapy, May 2006, p. 1813-1822, Vol. 50, No. 5
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.5.1813-1822.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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