Abstract
More than 20 years after the identification of the hepatitis C virus (HCV) as a novel human pathogen, the only approved treatment remains a combination of pegylated interferon-α and ribavirin. This rather non-specific therapy is associated with severe side effects and by far not everyone benefits from treatment. Recently, progress has been made in the development of specifically targeted antiviral therapy for HCV (STAT-C). A major target for such direct acting antivirals (DAAs) is the HCV RNA-dependent RNA polymerase or non-structural protein 5B (NS5B), which is essential for viral replication. This review will examine the current state of development of inhibitors targeting the polymerase and issues such as the emergence of antiviral resistance during treatment, as well as strategies to address this problem.
Highlights
With over 170 million people infected worldwide, the hepatitis C virus (HCV) represents a significant public health burden [1]
The HCV non-structural protein 5B (NS5B) polymerase is capable of initiating RNA synthesis de novo, i.e. in the absence of a primer, which is believed to be the mechanism of initiation in vivo [22,23,24,25,26]
nucleoside analogue inhibitors (NIs) and nucleoside analogue inhibitors (NNIs) that are designed to target HCV NS5B have distinct biochemical properties, which translates into different clinical challenges and opportunities
Summary
With over 170 million people infected worldwide, the hepatitis C virus (HCV) represents a significant public health burden [1]. The therapy currently available to those infected with HCV is a combination of ribavirin and pegylated IFN-α. Individuals infected with genotype 1, i.e. the most prevalent in North America and Europe, represent a “difficult-to-treat” population that respond poorly to treatment with ribavirin and pegylated IFN-α. Within each infected individual, HCV exists as a heterogeneous population of different viruses, referred to as quasispecies [9,10]. The HCV RNA-dependent RNA polymerase (RdRp) NS5B is error-prone and lacks proof-reading activity. Like the current standard of care, direct-acting antivirals can show a broad spectrum of activities depending on the genotype. This review will focus on NS5B polymerase inhibitors, with an attempt to bridge clinical and biochemical findings
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