Hepatitis C virus (HCV) NS5A protein supports the replication of HCV by interacting with viral and cellular proteins to form the HCV replicase complex, the micro-organelle that replicates HCV RNA, thus making it an excellent target for the discovery of anti-HCV therapeutics. Pibrentasvir is a novel and pan-genotypic HCV NS5A inhibitor with EC50 values ranging from 1.4 to 5.0 pM against HCV replicons containing NS5A from genotypes 1 to 6. Pibrentasvir inhibited HCV genotype 1a-H77, 1b-Con1, and 2a-JFH-1 subgenomic replicons with EC50 values of 1.8, 4.3 and 5.0 pM, respectively; EC50 values ranged between 1.4 and 2.8 pM against chimeric stable replicons containing NS5A derived from HCV genotypes 2a, 2b, 3a, 4a, 5a, and 6a. The 50% cytotoxicity concentration (CC50) value of pibrentasvir in an HCV genotype 1a replicon cell line was > 32,000,000 pM, producing an in vitro therapeutic index that exceeded 107-fold. Furthermore, pibrentasvir retained full activity against all of the genotype 1a and 1b single-position NS5A substitutions tested, except Y93H and Y93N of genotype 1a, which conferred ≤ 7-fold increase in EC50 to pibrentasvir (EC50 ≤ 5.1 pM)[3].
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