SCH 503034 Suppresses Polyprotein Maturation and Enhances the Antiviral Activity of Interferon Alfa-2b

The inhibition of NS3 activity in the HCV protease gene is expected to inhibit HCV replication by direct suppression of viral production and by the restoration of host interferon (IFN) responsiveness. The HCV protease inhibitor SCH 503034 reversibly binds the HCV NS3 protease and specifically inhibits its activity.

The anti-HCV activity of SCH 503034 may be enhanced by the immunomodulatory effects of peginterferon alfa-2b (PegIntron).

The effect of SCH 503034 on response to IFN was evaluated in replicon cells incubated with increasing amounts of SCH 503034 and IFN for 72 hours. Toxicity, was assessed by cell viability and doubling time.

Results

SCH 503034 inhibition of replicon synthesis was dose-related.
Exposure of replicon cells to SCH 503034 over 15 days resulted in log reductions in replicon RNA of approximately 2.0, 3.5, and 4.0 at 1.2, 6 and 12 x IC90, respectively.
No toxicity was seen after exposure

Based on these findings, the authors conclude, “SCH 503034 exhibited potent antiviral activity both alone and in combination with peginterferon alfa in the HCV replicon assay.”

Discussion

These results suggest that the combination of SCH 503034 with interferon alfa-2b may increase clinical effectiveness.

11/14/05

Reference
B A Malcolm and others. Preclinical and Early Clinical Development SCH 503034, a Mechanism-based Inhibitor of Hepatitis C Virus (HCV) NS3 Protease Suppresses Polyprotein Maturation and Enhances the Antiviral Activity of Interferon-á-2b (INF). Abstract 60227. 56^th annual meeting of the American Association for the Study of Liver Diseases (56^th AASLD). November 11-15, 2005. San Francisco, CA.