The molecular and structural basis of advanced antiviral therapy for hepatitis C virus infection

Key Points Hepatitis C virus (HCV) infection is a major cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma worldwide. Cell culture systems for HCV, especially the replicon and cell culture-derived HCV (HCVcc) systems, have been essential for researchers to gain insights into the viral replication cycle and for the development of selective drugs. Prime targets for direct-acting antiviral agents (DAAs) against HCV are the protease NS3-4A, the replicase factor NS5A and the RNA-dependent RNA polymerase NS5B. Knowledge of the biochemical and structural properties of NS3-4A, NS5A and NS5B has been a key factor for the development of highly efficient drugs targeting these proteins. Additional viral proteins, such as the ion channel formed by p7 or the membrane-active protein NS4B, represent alternative targets for antiviral therapy. Drugs directed against certain host cell factors on which HCV is dependent, such as cyclophilin A or microRNA miR-122, are highly efficient in vitro and in vivo . New drug regimens based on the combination of DAAs and independent of interferon and, eventually, ribavirin (both of which drugs account for serious side effects) appear to be within reach in the near future. Hepatitis C virus infection is a major cause of liver cirrhosis and cancer, and current therapies are often ineffective or have severe side effects. Here, Bartenschlager and colleagues review how structural and functional insights into the viral life cycle have allowed the development of novel direct-acting antiviral agents. The availability of the first molecular clone of the hepatitis C virus (HCV) genome allowed the identification and biochemical characterization of two viral enzymes that are targets for antiviral therapy: the protease NS3-4A and the RNA-dependent RNA polymerase NS5B. With the advent of cell culture systems that can recapitulate either the intracellular steps of the viral replication cycle or the complete cycle, additional drug targets have been identified, most notably the phosphoprotein NS5A, but also host cell factors that promote viral replication, such as cyclophilin A. Here, we review insights into the structures of these proteins and the mechanisms by which they contribute to the HCV replication cycle, and discuss how these insights have facilitated the development of new, directly acting antiviral compounds that have started to enter the clinic.