Elsevier

Advanced Drug Delivery Reviews

Volume 59, Issue 12, 10 October 2007, Pages 1277-1289
Advanced Drug Delivery Reviews

Modulation of host metabolism as a target of new antivirals

https://doi.org/10.1016/j.addr.2007.03.021Get rights and content

Abstract

The therapy for chronic hepatitis C (CH–C) started with interferon (IFN) monotherapy in the early 1990s and this therapy was considered effective in about 10% of cases. The present standard therapy of pegylated IFN with ribavirin achieves a sustained virologic response in about 50% of patients. However, about half of the CH–C patients are still at risk of fatal liver cirrhosis and hepatocellular carcinoma. The other significant event in hepatitis C virus (HCV) research has been the development of a cell culture system. The subgenomic replicon system enables robust HCV RNA replication in hepatoma cells. And recently, the complete life cycle of HCV has been achieved using a genotype 2a strain, JFH1. These hallmarks have provided much information about the mechanisms of HCV replication, including information on the host molecules required for the replication. Anti-HCV reagents targeting HCV proteins have been developed, and some of them are now in clinical trials. However, the RNA-dependent RNA polymerase frequently causes mutations in the HCV genome, which lead to the emergence of drug-resistant HCV mutants. Some of the cellular proteins essential for HCV RNA replication have already been discovered using the HCV cell culture system. These host molecules are also candidate targets for antivirals. Here, we describe the recent progress regarding the anti-HCV reagents targeting host metabolism.

Abbreviations

HCV
hepatitis C virus
CH
chronic hepatitis
HCC
hepatocellular carcinoma
IFN
interferon
SVR
sustained virological response
PEG-IFN
pegylated-IFN
GBV-B
GB virus B
uPA-SCID
urokinase plasminogen activator-severe combined immunodeficiency
NS
nonstructural
RdRp
RNA dependent RNA polymerase
CyPB
cyclophilin B
CsA
cyclosporine+ A
HSP90
heat shock protein 90
La
La auto antigen
PTB
polypyrimidine tract-binding protein
ALT
alanine aminotransferase
Neo
neomycin phosphotransferase
EMCV
encephalomyocarditis virus
IRES
internal ribosome entry site
ORF
open reading frame
FKBP8
FK-506-binding protein 8
GGPP
geranylgeranyl pyrophosphate
FPP
farnesyl pyrophosphate
FTase
farnesyltransferase
GGTase-I
geranylgeranyltransferase type I
GGTI
GGTase-I inhibitor
HMG–CoA
3-hydroxy-3-methylglutaryl coenzyme A
LOV
lovastatin
ATV
atorvastatin
FLV
fluvastatin
PRV
pravastatin
SMV
simvastatin
EC50
50%
effective concentration to inhibit HCV RNA replication
PTV
pitavastatin
RSV
respiratory syncytial virus
CMV
cytomegarovirus
HIV
human immunodeficiency virus
ICAM-1
integrin intercellular adhesion molecule 1
LFA-1
lymphocyte function associated antigen-1
DRM
detergent resistant membrane
SPT
serine palmitoyltransferase
ER
endoplasmic reticulum
GSL
glycosphingolipid
SBD
sphingolipid-binding domain
IMPDH
inosine monophosphate dehydrogenase
XMP
xanthosine 5′
monophosphate
MPA
mycophenolic acid
RMP
ribavirin monophosphate
RDP
ribavirin diphosphate
RTP
ribavirin triphosphate
GTP
guanosine triphosphate
SARS
severe acute respiratory syndrome
HBV
hepatitis B virus
VLP
virus-like particle
PIAS1
protein inhibitor of activated STAT1
PRMT1
protein arginine methyltransferase 1
PP2Ac
catalytic subunit of protein phosphatase 2A
AdoMet
S-adenosyl-L-methionine
PUFAs
polyunsaturated fatty acids
AA
arachidonic acid
DHA
docosahexaenoic acid
EPA
eicosapentaenoic acid
GLA
γ-linolenic acid

Keywords

Hepatitis C virus
Replicon
Antiviral
Interferon
Host metabolism
Statin

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This review is part of the Advanced Drug Delivery Reviews theme issue on “Toward Evidence Based Control of Hepatitis C Virus Infection”.

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