Combination therapy for hepatitis C virus with heat-shock protein 90 inhibitor 17-AAG and proteasome inhibitor MG132.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Ujino
Saneyuki
S
Department of Life and Environmental Sciences, Chiba Institute of Technology, Tsudanuma, Narashino, Chiba, Japan.
Yamaguchi
Saori
S
Shimotohno
Kunitada
K
Takaku
Hiroshi
H
D016227:Benzoquinones / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D006526:Hepatitis C / Q000188:drug therapy; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D007976:Leupeptins / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D061988:Proteasome Inhibitors; D012093:Replicon / Q000187:drug effects; D014162:Transfection; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics
D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D007976:Leupeptins; D061988:Proteasome Inhibitors; C112765:tanespimycin; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde