Anti-Viral Therapies for Hepatitis C Virus Infection: Current Options and Evolving Candidate Drugs

Abstract

Chronic hepatitis C is a ubiquitous disease, affecting approximately 170 million globally. The hepatitis C virus (HCV) is spread by parenteral transmission of body fluids, primarily blood or blood products. The hepatitis C viral genome is a positive-sense, single-stranded RNA molecule approximately 9.4kb in length, which encodes a polyprotein of about 3100 amino acids. There are 6 main genotypes of HCV, with each further stratified by subtype. Hepatitis C virus exists as a heterogeneous mixture of closely related viruses called quasispecies. The continuous evolution of new variant glycoproteins is a major mechanism of viral evasion of the immune system. The quasispecies diversity collapses to oligoclonality or homogeneity prior to clearance. Substantial evidence indicates that HCV genotype is clinically important with respect to efficacy of anti-viral therapy. The dual drug regime currently used to treat HCV infection consists of pegylated-interferon (peg-IFN) and the guanosine nucleoside analog ribavirin. Mutations in the viral genome are likely to contribute in large measure to the emergence of "resistance" during interferon-based therapy.The HCV genome codes for 10 proteins. The structural proteins of core, E1, E2 and P7 are positioned immediately downstream of the 5'UTR. These proteins are cleaved from the polyprotein by host-encoded proteases. The remaining proteins are released from the polyprotein by a process of autocatalytic cleavage or by the protease activity of NS3. The RNA dependent RNA polymerase (NS5B) is position immediately downstream of the 3'UTR. The current cytokine based treatment modality is based on a shotgun approach of up regulation of cellular anti-viral pathways. The net effect of IFN signalling is the down regulation of protein translation. The cellular signalling pathways induced by IFN engagement of the cognate receptor are not specific for the elimination of HCV. HCV has evolved mechanisms that hinder IFN signalling and the induction of nuclease activity that would otherwise destroy the viral genome. The net benefit to the virus is that it potentiates the establishment of persistence.The activity of the host encoded proteases necessary for the cleavage of Core-P7, the proteolytic activity of NS3, the helicase activity of NS3 and the polymerase activity of NS5B are all potential targets for the development of adjunct options for the treatment of hepatitis C virus infections. The development of novel antivirals suitable for use against HCV has learnt a great deal from the research and development of drugs used to treat HIV disease. Like HIV, HCV has the propensity to produce greater than 10 10 virions per day. Each genome will have a fitness potential to survive each unique selection pressure (endogenous and/or exogenous) and it is to be expected that again like HIV, HCV will have the potential to evolve drug resistant mutants. The goal of highly active antiretroviral therapy in HIV disease is viral suppression. However, it would appear that elimination, rather than suppression of vir...

Anti-HCV Bioactivity of Pseudoguaianolides from Parthenium hispitum

“…[7][8][9] The molecular weights of the new compounds 1-5 and their chemical formula were deduced from either positive or negative mode HRESIMS (Experimental Section). 1 H NMR data (Table 1) indicated that all five new compounds were esterified analogues at the C-14 hydroxy group of compound 6: n-propanoyl [1.13 (3H, t, J ) 7.3 Hz), 2.37 (2H, q, J ) 7.3 Hz)] in 1, n-butanoyl [0.96 (3H, t, J ) 7.4 Hz), 1.66 (2H, m), 2.32 (2H, t, J ) 7.3 Hz)] in 2, tigloyl [1.82 (3H, d, J ) 7.1 Hz), 1.84 (3H, brs), 6.88 (1H, q, J ) 7.1 Hz)] in 3, 3-methyl-2-butenoyl [1.92 (3H, brs), 2.17 (3H, brs), 5.71 (1H, brs)] in 4, and angeloyl [1.89 (3H, brs), 1.97 (3H, d, J ) 7.2 Hz), 6.14 (1H, q, J ) 7.2 Hz)] in 5. The COSY NMR, 13 C NMR (Table 2), and MS data were in full agreement with those moieties and the assignments.…”

“…The genus Parthenium is an herbaceous annual weed with noxiousness to other plants, humans, and animals. 5,6 P. hispitum has been found to yield two 1R-hydroxy-11(13)pseudoguaien-6β,12-olides, tetraneurin-C and tetraneurin-E. 7 In this paper, we report the semipreparative HPLC isolation (Figure 1) of five new (1)(2)(3)(4)(5) and four known (6-9) C 14 -oxygenated 1R-hydroxy-11(13)-pseudoguaien-6β,12-olides and their inhibition of HCV replication. The miniaturization of the structure elucidation and dereplication of these mass-limited pseudoguaianolides were performed primarily using a capillary-scale NMR probe and MS spectroscopic methods.…”

“…The hepatitis C virus (HCV) infects about 170 million people worldwide. , Millions of chronically infected patients develop cirrhosis requiring liver transplantation . Although treatments for HCV infection have been improved over the past several years, many infected people with genotype 1 virus have poor response to standard therapy and side effects remain a significant problem.…”

Development of a Novel Dicistronic Reporter-Selectable Hepatitis C Virus Replicon Suitable for High-Throughput Inhibitor Screening

“…Approximately 170 million people globally test positive for hepatitis C virus (HCV) (9,11). Infection by HCV results in a high degree of chronic hepatitis.…”