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Advanced Drug Delivery Reviews (v.59, #12)
HCV research and anti-HCV drug discovery: Toward the next generation
by Takaji Wakita (pp. 1196-1199).
Hepatitis C virus (HCV) causes persistent infection and induces chronic hepatitis, liver cirrhosis and finally hepatocellular carcinoma. Current therapies for HCV infection have not been satisfactory, and more effective anti-viral treatments are needed. In this regard, detailed analysis of HCV has been hampered by a lack of appropriate viral culture systems and small animal models of infection. However, rapid progress in HCV research has recently been achieved, such as a subgenomic replicon system, a viral culture system using JFH-1 clone and the Alb-uPA/SCID mouse transplanted with human liver cells. Such progress will propel HCV research and anti-HCV drug discovery toward the next generation.
Keywords: Hepatitis C virus; Anti-viral drug; Interferon; Ribavirin; Vaccine; Replicon; Virus culture
Hepatitis C viral life cycle
by Tetsuro Suzuki; Koji Ishii; Hideki Aizaki; Takaji Wakita (pp. 1200-1212).
Hepatitis C virus (HCV) has been recognized as a major cause of chronic liver diseases worldwide. Molecular studies of the virus became possible with the successful cloning of its genome in 1989. Although much work remains to be done regarding early and late stages of the HCV life cycle, significant progress has been made with respect to the molecular biology of HCV, especially the viral protein processing and the genome replication. This review summarizes our current understanding of genomic organization of HCV, features of the viral protein characteristics, and the viral life cycle.
Keywords: Hepatitis C virus; Translation; Polyprotein processing; RNA replication; Viral assembly
Evaluation systems for anti-HCV drugs
by Kohji Moriishi; Yoshiharu Matsuura (pp. 1213-1221).
Development of therapeutics for chronic hepatitis C has been hampered by the lack of an efficient cell culture system and a small animal model for the hepatitis C virus (HCV). An RNA replicon system, in which the HCV genome replicates autonomously in cells, and replication competent viruses derived from an HCV genotype 2a JFH1 strain efficiently propagating in Huh7 cells have been developed, and these systems have contributed to the evaluation of anti-HCV drugs targeted to viral and host proteins involved in the replication of HCV. Several compounds counteracting the viral enzymes, such as RNA polymerase and proteases, and host proteins involved in the lipid synthesis and protein folding are reported to have anti-HCV activities based on assessments using these in vitro systems. Furthermore, a mouse model transplanted with human liver fragments was shown to be capable of replicating HCV and has been used to evaluate the efficacy of antiviral drugs in vivo. In this review, we summarize information regarding systems for studying the HCV life cycle and potential new targets for therapeutic intervention for chronic hepatitis C.
Keywords: Anti-HCV drugs; Protease inhibitor; Nucleotide analogue; Cell-based model system; Animal model
Interferon-based therapy of hepatitis C
by Stéphane Chevaliez; Jean-Michel Pawlotsky (pp. 1222-1241).
In 2007, the world celebrated the 50th anniversary of the discovery of interferon (IFN). The first clinical trial of recombinant IFN–α in patients with chronic hepatitis C was published in 1986. This article reviews the classification of IFNs, IFN production during viral infections, IFN signaling pathways and the mechanisms of their antiviral and immunomodulatory properties. Hepatitis C virus infection treatment is currently based on the combination of pegylated IFN–α and ribavirin. The pegylated IFN–α molecules are described, as well as the putative mechanisms of action of ribavirin. Current treatment guidelines are discussed and new results suggesting that the treatment schedule should be tailored to the early virological response during therapy are presented. Finally, insights into new hepatitis C drug developments are given.
Keywords: Hepatitis C virus; Interferon; Ribavirin; Signaling pathways; Toll-like receptors; Virological response; Treatment tailoring
Advances in the development of new therapeutic agents targeting the NS3-4A serine protease or the NS5B RNA-dependent RNA polymerase of the hepatitis C virus
by Raffaele De Francesco; Andrea Carfí (pp. 1242-1262).
The HCV NS3 protease and NS5B polymerase play essential roles in the replication of the hepatitis C virus (HCV). Following the successful paradigm established for HIV protease and reverse transcriptase inhibitors, these enzymes have been elected as targets for the development of small molecule HCV inhibitors. By combining the power of high-throughput screening with rational, knowledge-based drug discovery, a number of competitive inhibitors of the NS3 protease as well as nucleoside and non-nucleoside inhibitors of the NS5B polymerase have been identified and some have now entered clinical trials. In this article we review recent progress in the discovery and development of small molecule inhibitors of these two essential viral enzymes as they are advancing in the clinic.
Keywords: Hepacivirus; Hepatitis C; Antiviral agents; Drug therapy; Drug resistance; Viral nonstructural proteins; Serine protease; RNA-dependent RNA polymerase; Enzyme inhibitors; Nucleoside analogues; Non nucleoside inhibitors; NNI; Allosteric inhibitors
Therapeutic application of RNA interference for hepatitis C virus
by Tsunamasa Watanabe; Takuya Umehara; Michinori Kohara (pp. 1263-1276).
RNA interference (RNAi) is a sequence-specific post-transcriptional gene silencing by double-stranded RNA. Because the phenomenon is conserved and ubiquitous in mammalian cells, RNAi has considerable therapeutic potential for human pathogenic gene products. Recent studies have demonstrated the clinical potential of logically designed small interfering RNA (siRNA). However, there are still obstacles in using RNAi as an antiviral therapy, particularly for hepatitis C virus (HCV) that displays a high rate of mutation. Furthermore, delivery is also an important obstacle for siRNA based gene therapy. This paper presents the potential applications and the hurdles facing anti-HCV siRNA drugs. The present review provides insight into the feasible therapeutic strategies of siRNA technology, and its potential for silencing genes associated with HCV disease.
Keywords: RNAi; HCV; siRNA; Therapeutics; Escape; Delivery
Modulation of host metabolism as a target of new antivirals
by Masanori Ikeda; Nobuyuki Kato (pp. 1277-1289).
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.
Keywords: 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; EC; 50; 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 acidHepatitis C virus; Replicon; Antiviral; Interferon; Host metabolism; Statin
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