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Combinations of 2'-C-methylcytidine Analogues With interferon-alpha2b and Triple Combination With Ribavirin in the Hepatitis C Virus Replicon System

Combinations of 2'-C-methylcytidine Analogues With interferon-alpha2b and Triple Combination With Ribavirin in the Hepatitis C Virus Replicon System

Leda Bassit, Jason Grier, Matthew Bennett, Raymond F Schinazi

Antivir Chem Chemother. 2008;19(1):25-31.

PMID: 18610555

Abstract:

Background:
Hepatitis C virus (HCV) polymerase is an essential enzyme for HCV replication and has multiple inhibitor binding sites making it a major target for antiviral intervention. It is apparent that no single drug can inhibit HCV replication in humans. Hence, combinations of nucleoside analogues beta-D-2'-C-methylcytidine (2'-C-MeC; NM-107) or beta-D-2'-deoxy-2'-fluoro-2'-C-methyleytidine (2'-F-C-MeC; PSI-6130) with interferon-alpha2b (IFN-alpha2b) or triple combination with ribavirin (RBV) were evaluated.
Methods:
Huh-7 cells containing the self-replicating subgenomic HCV replicon (Clone B) were used for drug combination studies. After drug treatment for 5 days, total cellular RNA was then extracted and both ribosomal RNA and HCV replicon RNA were amplified in a single-step multiplex real-time PCR assay. Drug interaction analyses were performed using the CalcuSyn program.
Results:
Double combinations of 2'-C-MeC or 2'-F-C-MeC with IFN-alpha2b at all ratios tested had weighted average combination index (Cl(wt)) values <1 indicating synergistic inhibition of HCV replication in the replicon system. For the triple combinations of IFN-alpha2b plus RBV with either 2'-C-MeC or 2'-F-C-MeC, the Cl(wt) values at 1:1:1 ratio tested were 0.5 and 0.8, respectively, indicating synergistic antiviral effects. No apparent cytotoxicity effects were observed with any of the combinations tested.
Conclusion:
These promising in vitro data warrant clinical investigation of the nucleosides analogues such as 2'-C-MeC or 2'-F-C-MeC in their prodrug forms, together with IFN-alphac2b and RBV, for successful treatment of HCV infections.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP20724736	2'-C-Methylcytidine		20724-73-6	Price

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