New antiviral therapies in the management of HCV infection
ABSTRACT Improved knowledge of the HCV life cycle and of structural features of HCV proteins have led to the discovery of numerous potential targets for antiviral therapy. Viral replication and polyprotein processing have been tagged as promising viral targets. Clathrin-mediated endocytosis, fusion of HCV with cellular membranes, translation of viral RNA, virus production and release as well as several host cell factors may provide alternative targets for future anti-HCV therapies. Several compounds are currently under investigation in clinical trials and showed high antiviral activity in patients with chronic hepatitis C. Recently, Phase III studies for two protease inhibitors, telaprevir and boceprevir, each given in combination with pegylated interferon (standard of care [SOC]), were completed. In HCV-genotype-1-infected patients, the addition of telaprevir or boceprevir to SOC increased sustained virological response rates from <50% to >70%. Nucleoside/nucleotide inhibitors of the HCV NS5B polymerase have shown antiviral activity against different HCV genotypes, and have a higher barrier to resistance than protease inhibitors. In addition, several allosteric binding sites have been identified for non-nucleoside inhibitors of the NS5B polymerase. Inhibitors of NS5A are potentially active against all HCV genotypes. Among the different host cell-targeting compounds, cyclophilin inhibitors have shown promising results. Future hope lies in the combination of direct-acting antiviral agents with the possibility of interferon-free treatment regimens.
- SourceAvailable from: Zhinan Jin[Show abstract] [Hide abstract]
ABSTRACT: Hepatitis C virus (HCV) RNA-dependent RNA polymerase replicates the viral genomic RNA and is a primary drug target for antiviral therapy. Previously, we described the purification of an active and stable polymerase-primer-template elongation complex. Here, we show that, unexpectedly, the polymerase elongation complex can use NTPs to excise the terminal nucleotide in nascent RNA. Mismatched ATP, UTP, or CTP could mediate excision of 3'-terminal CMP to generate the dinucleoside tetraphosphate products Ap(4)C, Up(4)C, and Cp(4)C, respectively. Pre-steady-state kinetic studies showed that the efficiency of NTP-mediated excision was highest with ATP. A chain-terminating inhibitor, 3'deoxy-CMP, could also be excised through this mechanism, suggesting important implications for nucleoside drug potency and resistance. The nucleotide excision reaction catalyzed by recombinant hepatitis C virus polymerase was 100-fold more efficient than the corresponding reaction observed with HIV reverse transcriptase.Proceedings of the National Academy of Sciences 01/2013; DOI:10.1073/pnas.1214924110 · 9.81 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Recently, graphene oxide (GO), one of the carbon nanomaterials, has received much attention due to its unique physical and chemical properties and high potential in many research areas including applications as biosensors and drug delivery vehicle. Various GO-based biosensors, largely based on its surface adsorption properties, have been developed not only for the detection of biomolecules including nucleotides and peptides, but also for the realtime monitoring of enzymatic reactions. In this review, we discuss recent advances of GO-based biosensors focusing on a novel assay platform for helicase activity, which was also employed for high-throughput screening to discover selective helicase inhibitors.Moleculer Cells 03/2013; 35(4). DOI:10.1007/s10059-013-0066-1 · 2.24 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: There is ample epidemiologic evidence for an association of chronic hepatitis C virus (HCV) infection with B-cell non-Hodgkin Lymphoma (B-NHL). B-NHL subtypes most frequently associated with HCV are marginal zone lymphoma and diffuse large B-cell lymphoma. The most convincing evidence for a causal relationship between HCV infection and lymphoma development is the observation of B-NHL regression after HCV eradication by antiviral therapy (AVT). In fact, for indolent HCV-associated B-NHL, first-line AVT instead of standard immune-chemotherapy might be considered. Molecular mechanisms of HCV-NHL development are still poorly understood. Three general theories have emerged to understand the HCV-induced lymphomagenesis: 1. Continous external stimulation of lymphocyte receptors by viral antigens and consecutive proliferation; 2. HCV replication in B-cells with oncogenic effect mediated by intracellular viral proteins; 3. Permanent B-cell damage, e.g. mutation of tumor suppressor genes, caused by a transiently intracellular virus ("hit and run" theory). This review systematically summarizes the data on epidemiology, interventional studies and molecular mechanisms of HCV-associated B-NHL.Journal of Hepatology 03/2013; 49(1). DOI:10.1016/j.jhep.2013.03.018 · 10.40 Impact Factor