[BILN 2061 -- Resistance profile]
>>Antimicrob Agents Chemother. 2004 Jun;48(6):2260-6.
Mutations conferring resistance to a potent hepatitis C virus serine protease inhibitor in vitro.
Lu L, Pilot-Matias TJ, Stewart KD, Randolph JT, Pithawalla R, He W, Huang PP, Klein LL, Mo H, Molla A.
Antiviral Research, Abbott Laboratories, Global Pharmaceutical Research and Development, Abbott Park, IL 60064-6217, USA. liangjun.lu@abbott.com
BILN 2061 is a novel, specific hepatitis C virus (HCV) NS3 serine protease inhibitor discovered by Boehringer Ingelheim that has shown potent activity against HCV replicons in tissue culture and is currently under clinical investigation for the treatment of HCV infection. The poor fidelity of the HCV RNA-dependent RNA polymerase will likely lead to the development of drug-resistant viruses in treated patients. The development of resistance to BILN 2061 was studied by the in vitro passage of HCV genotype 1b replicon cells in the presence of a fixed concentration of the drug. Three weeks posttreatment, four colonies were expanded for genotypic and phenotypic characterization. The 50% inhibitory concentrations of BILN 2061 for these colonies were 72- to 1,228-fold higher than that for the wild-type replicon. Sequencing of the individual colonies identified several mutations in the NS3 serine protease gene. Molecular clones containing the single amino acid substitution A156T, R155Q, or D168V resulted in 357-fold, 24-fold, and 144-fold reductions in susceptibility to BILN 2061, respectively, compared to the level of susceptibility shown by the wild-type replicon. Modeling studies indicate that all three of these residues are located in close proximity to the inhibitor binding site. These findings, in addition to the three-dimensional structure analysis of the NS3/NS4A serine protease inhibitor complex, provide a strategic guide for the development of next-generation inhibitors of HCV NS3/NS4A serine protease.<<
emphasis mine
Points to a) why BI is looking at other classes, and b) the need for an approach that dodges resistance. The holy grail of anti-viral research. Interesting that this work comes from Abbott, as if taking a shot across BI's bow.
Cheers, Tuck |
