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This viral polyprotein is expressed by way of an internal ribosome entry site encoded at the 5′ end of the HCV genome which folds into intricate secondary structures, thus directly recruiting cellular ribosomes to the viral RNA to initiate translation. The HCV-positive strand viral RNA genome is depicted at the top.
Several co- and post-translational cleavage steps mediated by both host and viral proteases liberate ten distinct viral proteins, namely core, envelope proteins 1 and 2, p7, NS2, NS3, NS4A, NS4B, NS5A and NS5B proteins (fig. 5′- and 3′-terminal genome portions are not translated regions (NTRs), which fold into extensive secondary structures needed for genome replication and translation.
Selection of these two viral proteins as targets for development of antivirals was favorable for several reasons.
First, recombinant purified and enzymatically active proteins were available relatively early, tests to evaluate enzymatic function were rapidly developed and the respective crystal structures were obtained.
The variability of HCV allows immune evasion and facilitates persistence.
It is also a substantial challenge for the development of specific antiviral therapies effective across all HCV genotypes and for prevention of drug resistance.
The recent development of HCV cell culture systems (see below) not only provided the urgently needed armamentarium to identify and validate the most promising DAAs, it was also instrumental for characterization of numerous cellular factors that aid in HCV propagation.Therefore, current drug development includes both targeting of viral factors but also of host factors essential for virus replication.In fact, some of these host-targeting agents, for instance inhibitors of cyclophilin A, have advanced to late stage clinical trials.Translation of these observations into safe and efficacious treatments is, however, many steps away in most cases.Nevertheless, HIV-1 inhibitors, which target host-encoded chemokine receptors thus precluding viral cell entry, provide proof of concept that safe and well-tolerated HTAs can be developed.