Inhibition of hepatitis C virus by nucleic acid-based antiviral approaches

Abstract

Persistent infection with the hepatitis C virus (HCV) is a major cause of acute and chronic liver disease and frequently leads to liver cirrhosis and hepatocellular carcinoma. Current treatment is based on a combination therapy with polyethylene glycol-conjugated interferon-alpha and ribavirin, but efficacy is limited and treatment is associated with severe side-effects. More efficient and selective drugs are therefore needed. Apart from small molecule inhibitors targeting the viral key enzymes, especially the NS3 proteinase and the NS5B RNA-dependent RNA polymerase, nucleic acid (NA)-based antiviral intervention is an attractive option. Originally, antisense oligonucleotides and ribozymes targeting highly conserved regions in the HCV genome have been developed. More recently, short interfering RNAs (siRNAs) were shown to potently block HCV RNA replication in cell culture. However, the high degree of sequence diversity between different HCV genotypes, the rapid evolution of quasispecies and the delivery of antivirally active NAs are challenging problems of NA-based therapies. Here, we will review the current state of NA-based approaches designed to interfere with HCV replication.