PSI-7977

PSI-7977 (sofosbuvir) is an investigational nucleotide analog for treatment of chronic HCV infection. PSI-7977 (GS-7977) is a uridine nucleotide analog as HCV NS5B polymerase inhibitor for the treatment of chronic hepatitis C virus (HCV) infection. PSI-7977 is a more potent inhibitor of HCV RNA replication than PSI-7976. When CatA is incubated with PSI-7977 or PSI-7976, ~18-fold more PSI-352707 is formed when PSI-7977 is the substrate compared with PSI-7976, and the catalytic efficiency for PSI-7977 with CatA is ~30-fold higher than that for PSI-7976. However, CES1 preferentially hydrolyzes PSI-7976 over PSI-7977. Incubating clone A cells with PSI-7977 results in a higher concentration of PSI-7409 than that with PSI-7976. NS5B polymerase S282T mutation but not S96T mutation is resistant to PSI-7977 with EC90 of 7.8 μM. PSI-7977 has no cytotoxicity against Huh7, HepG2, BxPC3, and CEM cells even at concentrations up to 100 μM. PSI-7977 is active against genotype (GT) 1a, 1b, and 2a (strain JFH-1) replicons and chimeric replicons containing GT 2a (strain J6), 2b, and 3a NS5B polymerase. Cross-resistance studies using GT 1b replicons confirme that the S282T change conferres resistance to PSI-7977. Data from the JFH-1 replicon variants show that amino acid changes within the finger and palm domains together with S282T are required to confer resistance to PSI-7977, while the mutations on the thumb domain serve to enhance the replication capacity of the S282T replicons. PSI-7977 is currently being investigated in phase 3 clinical trials for the treatment of hepatitis C.