Hepatitis C RNA-dependent RNA polymerase inhibitors: a review of structure-activity and resistance relationships; different scaffolds and mutations.

Hepatitis C virus (HCV), like many other flaviviruses, is widely distributed worldwide with estimated chronically infected victims between 170 and 200 million. HCV inherent error-prone RNA-dependent RNA polymerase (RdRp) is an attractive target for medicinal chemists because of the conservative nature of NS5B nucleotide-binding site. In addition, the availability of several crystal structures for HCV RdRp paved the road for conducting rational-based drug design. At the same time, RdRp is responsible for high mutation rate and rapid development of resistance to the clinically-used therapeutics. To improve the viral response, combination therapy is regularly used. The success of co-therapy disciplines depends on targeting two different active sites. This review provides an overview about different scaffolds that target HCV RdPp with insights about their binding modes and possible induced mutant strains. Published by Elsevier Ltd.