benzyloxycarbonylleucyl-leucyl-leucine-aldehyde and Hepatitis-C

The ubiquitin proteasome system plays important role in virus infection. A previous study showed that the proteasome inhibitor MG132 could potentially affect hepatitis E virus (HEV) replication. In this study, we found that MG132 could inhibit HEV and hepatitis C virus (HCV) replication-related luciferase activity in subgenomic models. Furthermore, treatment with MG132 in a HEV infectious model resulted in a dramatic reduction in the intracellular level of HEV RNA. Surprisingly, MG132 concurrently inhibited the expression of a luciferase gene used as a control as well as a wide range of host genes. Consistently, the total cellular RNA and protein content was concurrently reduced by MG132 treatment, suggesting a nonspecific antiviral effect.

Topics: Antiviral Agents; Cell Line, Tumor; Cysteine Proteinase Inhibitors; Hepacivirus; Hepatitis C; Hepatitis E; Hepatitis E virus; Humans; Leupeptins; Proteasome Inhibitors; RNA, Viral; Virus Replication

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease. Here, we report a new and effective strategy for inhibiting HCV replication using an inhibitor of heat-shock protein 90, 17-AAG (17-allylamino-17demethoxygeldanamycin), and a proteasome inhibitor, MG132.. To explore the virological basis of combination therapy, we analysed the effects of 17-AAG and MG132, singly and in combination on HCV replication in an HCV replicon cell system.. In HCV replicon cells, HCV RNA replication was suppressed by 17-AAG in a dose-dependent manner. As shown in the present study, the 50% inhibitory concentration values were 0.82 nM for 17-AAG and 0.21 nM for MG132. Low concentrations of MG132 had strong synergistic inhibitory effects with low toxicity on HCV replicon cells.. The results of this study suggest that the different effects and synergistic actions of 17-AAG and MG132 could provide a new therapeutic approach to HCV infection.

Topics: Benzoquinones; Cell Line, Tumor; Drug Synergism; Drug Therapy, Combination; Hepacivirus; Hepatitis C; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Leupeptins; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Replicon; Transfection; Virus Replication