Genotype and Subtype Profiling of PSI-7977 as a Nucleotide Inhibitor of Hepatitis C Virus

摘要: PSI-7977, a prodrug of 2′-F-2′-C-methyluridine monophosphate, is the purified diastereoisomer PSI-7851 and currently being investigated in phase 3 clinical trials for treatment hepatitis C. In this study, we profiled activity PSI-7977 its ability to select resistance using number different replicon cells. Results showed that was active against genotype (GT) 1a, 1b, 2a (strain JFH-1) replicons chimeric containing GT J6), 2b, 3a NS5B polymerase. Cross-resistance studies 1b confirmed S282T change conferred PSI-7977. Subsequently, evaluated (JFH-1) common mutation selected among all three genotypes, but while it 1a JFH-1 only very modest shift 50% effective concentration (EC50) Sequence analysis region indicated additional amino acid changes were both prior after emergence S282T. These include T179A, M289L, I293L, M434T, H479P. Residues 179, 289, 293 are located within finger palm domains, 434 479 on surface thumb domain. Data from variants domains together with required confer mutations domain serve enhance replication capacity replicons.