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A more recent version of this article appeared on November 4, 2005 Originally published In Press as doi:10.1074/jbc.M506462200 on August 8, 2005
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Papers In Press, published online ahead of print September 12, 2005
J. Biol. Chem, 10.1074/jbc.M506462200
Submitted on June 14, 2005
Revised on July 20, 2005
Accepted on August 8, 2005

In vitro studies of cross-resistance mutations against two hepatitis C virus serine protease inhibitors, VX-950 and BILN 2061

Chao Lin, Cynthia A. Gates, B. Govinda Rao, Debra L. Brennan, John F. Fulghum, Yu-Ping Luong, J. Daniel Frantz, Kai Lin, Sue Ma, Yun-Yi Wei, Robert B. Perni, and Ann D. Kwong

Department of Infectious Diseases Biology, Vertex Pharmaceuticals Incorporated, Cambridge, MA 02139

Corresponding Author: chao_lin{at}vrtx.com

VX-950 is a potent, small-molecule, peptidomimetic inhibitor of the hepatitis C virus (HCV) NS3•4A serine protease, which has recently demonstrated antiviral efficacy in a phase I trial in patients chronically infected with genotype 1 HCV. In a previous study, we described in vitro resistance mutations against either VX-950 or another HCV NS3•4A protease inhibitor, BILN 2061, which has also demonstrated antiviral activity in phase I clinical trials in hepatitis C patients. Single amino acid substitutions were identified in the HCV NS3 serine protease domain that conferred drug resistance, distinct for either inhibitor. The dominant resistance mutation against VX-950, A156S, remains sensitive to BILN 2061. The major BILN 2061-resistant mutations, D168V and D168A, are fully susceptible to VX-950. Modeling analysis suggested that there are different mechanisms of resistance for these mutations, induced by VX-950 or BILN 2061, respectively. In the current study, we identified mutations that are cross-resistant to both HCV protease inhibitors. The cross-resistance conferred by substitutions of Ala156 with either Val or Thr was confirmed by characterization of the purified enzymes and reconstituted replicon cells that contain the single amino acid substitution, A156V or A156T. Both cross-resistance mutations, A156V and A156T, displayed significantly diminished fitness (or replication capacity) in a transient replicon cell system.


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