HCV

Hepatitis C virus (HCV) is a positive-strand RNA virus grouped in the genus Hepacivirus within the family Flaviviridae. HCV is classified into at least 6 genotypes (gt), and its error-prone polymerase leads to more than 50 subtypes. The long open reading frame, which encodes the HCV polyprotein, is processed by host and viral proteases and gives rise to three structural proteins (the capsid protein core and envelope glycoproteins E1 and E2) and seven nonstructural (NS) proteins (p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B). NS2 and p7 are essential for virus assembly but not RNA replication, whereas NS3 to NS5B are involved in a membrane-associated RNA replicase complex (RC). The NS3 protein is composed of a serine protease and an RNA helicase/nucleoside triphosphatase (NTPase), NS4A serves as a cofactor for NS3 serine protease, NS5B is the RNA-dependent RNA polymerase, and NS5A is considered to play key roles in multiple steps of the HCV life cycle.NS5A inhibitors exhibit a rapid inhibition of virus infectivity shortly after administration to HCV-infected cells.

The HCV protein NS5A prevents the apoptosis-enabling loss of intracellular potassium by inhibiting Kv2.1 function and thus blocking hepatocyte cell death.

The HCV RNA-dependent RNA polymerase (RdRp) has long been a prime target for antiviral development because of its critical role in viral replication and the absence of a mammalian homologous enzyme.

The combination of lucidone and alpha interferon, the protease inhibitor Telaprevir, the NS5A inhibitor BMS-790052, or the NS5B polymerase inhibitor PSI-7977, synergistically suppresses HCV RNA replication.