New targets for antiviral therapy of chronic hepatitis C

Until recently, chronic hepatitis C caused by persistent infection with the hepatitis C virus (HCV) has been treated with a combination of pegylated interferon-alpha (PEG-IFNa) and ribavirin (RBV). This situation has changed with the development of two drugs targeting the NS3/4A protease, approved for combination therapy with PEG-IFNa/RBV for patients infected with genotype 1 viruses. Moreover, two additional viral proteins, the RNA-dependent RNA polymerase (residing in NS5B) and the NS5A protein have emerged as promising drug targets and a large number of antivirals targeting these proteins are at different stages of clinical development. Although this progress is very promising, it is not clear whether these new compounds will suffice to eradicate the virus in an infected individual, ideally by using a PEG-IFNa/RBV-free regimen, or whether additional compounds targeting other factors that promote HCV replication are required. In this respect, host cell factors have emerged as a promising alternative. They reduce the risk of development of antiviral resistance and they increase the chance for broad-spectrum activity, ideally covering all HCV genotypes. Work in the last few years has identified several host cell factors used by HCV for productive replication. These include, amongst others, cyclophilins, especially cyclophilinA (cypA), microRNA-122 (miR-122) or phosphatidylinositol-4-kinase III alpha. For instance, cypA inhibitors have shown to be effective in combination therapy with PEG-IFN/RBV in increasing the sustained viral response (SVR) rate significantly compared to PEG-IFN/RBV. This review briefly summarizes recent advances in the development of novel antivirals against HCV.