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.
|Cell lines||Huh7, HepG2, BxPC3, and CEM|
|Preparation method||Exposing cells to various concentrations of PSI-7977 for 8 days. At the end of the growth period, adding MTS dye from the CellTiter 96 AQueous One Solution Cell Proliferation Assay kit to each well, and incubating the plate for an additional 2 hours. Read the absorbance at 490 nm with a Victor3 plate reader using themedium only controlwells as blanks. determing the 50% inhibition value (IC50) by comparing the absorbance in wells containing cells and PSI-7977 to untreated cell control wells.|
|Concentrations||Dissolved in DMSO, final concentrations ~100 μM|
|Incubation time||8 days|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
|Solubility||DMSO 80 mg/mL
Water 9 mg/mL
Genotype and subtype profiling of PSI-7977 as a nucleotide inhibitor of hepatitis C virus.
Lam AM1, et al. Antimicrob Agents Chemother. 2012 Jun;56(6):3359-68. PMID: 22430955.
Synthesis of stable isotope labeled analogs of the anti-hepatitis C virus nucleotide prodrugs PSI-7977 and PSI-352938.
Chun BK, et al. Nucleosides Nucleotides Nucleic Acids. 2011 Nov;30(11):886-96. PMID: 22060553.
Discovery of a β-d-2'-deoxy-2'-α-fluoro-2'-β-C-methyluridine nucleotide prodrug (PSI-7977) for the treatment of hepatitis C virus.
Sofia MJ, et al. J Med Chem. 2010 Oct 14;53(19):7202-18. PMID: 20845908.
Mechanism of activation of PSI-7851 and its diastereoisomer PSI-7977.
Murakami E, et al. J Biol Chem. 2010 Nov 5;285(45):34337-47. PMID: 20801890.
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