Combinations of 2'-C-methylcytidine analogues with interferon-alpha2b and triple combination with ribavirin in the hepatitis C virus replicon system.
Antivir Chem Chemother
; 19(1): 25-31, 2008.
Article
em En
| MEDLINE
| ID: mdl-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 111 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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Antivirais
/
Ribavirina
/
Interferon-alfa
/
Hepacivirus
/
Desoxicitidina
Tipo de estudo:
Health_economic_evaluation
Limite:
Humans
Idioma:
En
Revista:
Antivir Chem Chemother
Assunto da revista:
QUIMICA
/
TERAPIA POR MEDICAMENTOS
/
VIROLOGIA
Ano de publicação:
2008
Tipo de documento:
Article
País de afiliação:
Estados Unidos