Combining
Experimental HCV Inhibitors Boceprevir and NM 107 Enhances Anti-HCV Activity and
Suppresses Emergence of Resistance Combinations of small-molecule antiviral agents for the treatment of hepatitis
C virus (HCV infection) -- particularly those with different molecular targets
-- offer the potential for enhanced suppression of HCV replication and reduced
emergence of drug resistance.
Boceprevir (SCH
503034), a NS3 HCV
protease inhibitor from Schering-Plough, and valopicitabine
(NM 283), a nucleoside NS5B polymerase inhibitor from Idenix/Novartis,
have demonstrated antiviral activity in clinical studies, although resistant viral
variants have been detected. In the current study, presented at the 42nd Annual Meeting of the European Association for the Study of the Liver this week in Barcelona, Spain, the combined antiviral effects
of boceprevir and NM 107, the active prodrug of valopicitabine, were assessed
using a cell culture HCV replicon system. The combined antiviral effect
of boceprevir and NM 107 was evaluated in genotype
1b HCV replicon cells using real time RT-PCR or ELISA. Possible
cross-resistance of these compounds
was evaluated using replicon variants carrying single amino acid substitutions
(T54A, A156S, V170A, A156T) in the HCV protease that reduce susceptibility to
boceprevir, and NM107-resistant replicons carrying the S282T substitution in the
HCV polymerase. These substitutions in the HCV protease and polymerase reduced
inhibitory potency 5- to 125-fold for boceprevir and NM 107, respectively. 
Figure
1. Structures of boceprevir and NM 107 (active moiety of NM283) Results
- The
combination of boceprevir and NM 107 showed dose-dependent
enhancement of replicon inhibition, compared
with the effect of each inhibitor used alone.
- Reductions
in levels of both replicon RNA and protein were observed.
- No cytotoxicity
was observed.
- Cross-resistance was not observed.
- Boceprevir
showed similar activity against wild-type and NM 107-resistant replicons.
- The
combination of boceprevir and NM 107 significantly
reduced the frequency of resistant colonies in a dose-dependent manner, compared
to each inhibitor used alone.
Schering-Plough
Research Institute, Kenilworth, NJ; Idenix Pharmaceuticals, Cambridge, MA. 04/13/07 Reference
R Ralston, V Bichko, R Chase, and others. Combination of Two Hepatitis C
Virus Inhibitors, SCH 503034 (boceprevir) and NM107 (Active Moiety of Valopicitabine), Provides Enhanced Anti-Replicon
Activity and Suppresses Emergence of Resistant Replicons. 42nd Annual Meeting
of the European Association for the Study of the Liver. April
11 - 15, 2007, Barcelona,
Spain.
|
