Resistance Mutations Against HCV Protease Inhibitors and Antiviral Drug Design

The treatment for hepatitis C virus (HCV) infection has been significantly improved with the approval of the first two HCV NS3/4A protease inhibitors, telaprevir (Incivek) and boceprevir (Victrelis). These two direct acting antivirals (DAAs) are used clinically in combination with pegylated interferon-alpha (PEG-IFN alpha) and ribavirin (RBV). The sustained virologic response (SVR) rates are increased to similar to 70% and the duration of the treatment is similar to 50% shorter among treatment-naive patients with genotype 1 HCV. Variants (quasi species) are almost constantly introduced during HCV replication due to its rapid replication rate and the low fidelity of its polymerase. Drug resistant variants carrying mutations that affect the binding of DAAs have the growth advantage over wild-type virus and could become the dominant viral quasi species during treatment with DAAs. Mutations at a number of key positions of the NS3/4A protease have been reported to be associated with drug resistance. This review summarizes the mutations that are responsible for resistance against the two approved protease inhibitors and several compounds in advanced clinical trials. The impacts of the resistance mutations on the binding of the inhibitors as well as the design of next-generation protease inhibitors are discussed from the perspective of medicinal chemistry.