Antiviral therapy for hepatitis C virus: beyond the standard of care

Abstract

Hepatitis C virus (HCV) represents a major health burden, with an estimated 180 million chronically infected individuals worldwide. These patients are at increased risk of developing liver cirrhosis and hepatocellular carcinoma. Infection with HCV is the leading cause of liver transplantation in the Western world. Currently, the standard of care (SoC) consists of pegylated interferon alpha (pegIFN-α) and ribavirin (RBV). However this therapy has a limited efficacy and is associated with serious side effects. Therefore more tolerable, highly potent inhibitors of HCV replication are urgently needed. Both Specifically Targeted Antiviral Therapy for HCV (STAT-C) and inhibitors that are believed to interfere with the host-viral interaction are discussed.

Keywords: HCV; new antivirals; review.

Figure 1.

New antivirals for the treatment of HCV and current stage of development.

Figure 2.

Binding sites for HCV polymerase inhibitors. This figure is created using Chimera [105] based on superposition of different pdb structures using the Dali server [106]. The superimposed structures are 1GX6 (active site with UTP), 2BRK (with benzimidazole in thumb domain site 1), 1OS5 (with dihydropyranone in thumb domain 2 site), 1YVF (with benzothiadiazine in palm domain site 1), 3FQL (with benzofuran in the palm domain site 2). The palm, fingers and thumb domains are colored blue, yellow and red respectively. UTP and benzofuran have yellow carbons, the other molecules green carbons. Mn++ ions in the active site are grey. Mutations in different regions have a different color: salmon for residues P495, P496, V499 in thumb domain 1, magenta for L419, M423, I482 in thumb domain 2, gold for N411, M414 in palm domain 1, cyan for C316, S365 in palm domain 2, green for C445, Y448, Y452 in the beta-hairpin loop.