Modulation of host metabolism as a target of new antivirals

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.

Fig. 1

Gene organizations of HCV and selectable HCVs. HCV ORF, untranslated regions, EMCV IRES, and Neo are depicted as shaded boxes, thin lines, thick lines, and open boxes, respectively. ΔC indicates the 12 N-terminal amino acid residues of the core as a part of IRES.

Fig. 2

Inhibitory effect of statin on HCV RNA replication in OR6 cells. (A) Schematic gene organization of genome-length HCV RNA (ORN/C-5B/KE) derived from genotype 1b, strain O. The Renilla luciferase gene, which is symbolized as RL, is depicted as a striped box and is expressed as a fusion protein with Neo. The adaptive mutation from lysine (K) to glutamine (E) at amino acids position 1609 was previously reported and introduced into the genome-length HCV RNA. (B) Inhibition of HCV RNA by PTV. OR6 cells were cloned cell line selected by G418 . OR6 cells were treated with PTV at a concentration of 0, 0.156, 0.31, 0.625, 1.25, 2.5, or 5 μM. After 72 hours of treatment the RL activities were determined. Shown here is the relative RL activity (%) calculated when the RL activity of untreated cells was assigned as 100%. The data indicate the means ± standard deviation from three independent experiments. The EC₅₀ of PTV was determined as 0.45 μM.

Fig. 3

Cholesterol-biosynthesis pathway. The inhibition of HMG–CoA reductase by statins leads to the suppression of mevalonate and of the production of its downstream metabolites. Decreased prenylation on the GTP-binding proteins had a significant effect on the signal transduction.

Fig. 4

Sphingolipid-biosynthesis pathway. The spingolipid-biosynthesis pathway. Myriocin and NA255 inhibited the SPT and caused the depletion of spingomyelin and glycosphingolipids.

Fig. 5

GTP-biosynthesis pathway. The de novo GTP-biosynthesis pathway. Ribavirin, mizoribine, and MPA suppressed the XMP synthesis by the inhibition of IMPDH.

Fig. 6

Fatty acid-biosynthesis pathway. The PUFA metabolism from diet or membrane phospholipids.