Related Experiment Video
Updated: May 11, 2026

Reverse Genetics to Engineer Positive-Sense RNA Virus Variants
Published on: June 9, 2022
Resistance mutations against HCV protease inhibitors and antiviral drug design
Luqing Shang, Kai Lin, Zheng Yin1
1College of Pharmacy & State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, PR China. kai.lin@ymail.com.
Abstract:
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-IFNα) and ribavirin (RBV). The sustained virologic response (SVR) rates are increased to ~70% and the duration of the treatment is ~50% shorter among treatment-naïve 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.
Related Concept Videos
Viral Mutations
Retrovirus Life Cycles
Inhibitors of Viral Protein Synthesis
Hepatitis
Pharmacogenomics: Identification of New Drug Targets
Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu

