TABLE 1.

Antiviral and cytotoxicity effects of antimetabolites on HCV replicon-transfected Huh-7 cells

Compoundlog10 RNA reductiona at 100 μM for:Corrected HCV RNA
HCVrRNAlog10 reductiona at 100 μMlog10 reduction at 10 μMEC90, μM
IMPDH inhibitors (EC 1.1.1.205)
    Mizoribine0.29 ± 0.740.21 ± 0.500.08 ± 0.82−0.14 ± 0.12>100
    Tiazofurin0.86 ± 0.270.99 ± 0.35−0.13 ± 0.370.04 ± 0.10>100
    Mycophenolic acid1.15 ± 0.431.09 ± 0.280.07 ± 0.470.22 ± 0.01>100
    C2-MAD1.09 ± 0.211.00 ± 0.150.08 ± 0.240.36 ± 0.21>100
Ribonucleotide reductase inhibitors (EC 1.17.4.1; EC 1.17.4.2)
    Guanazole0.25 ± 0.110.07 ± 0.030.32 ± 0.080.05 ± 0.08>100
    Hydroxyurea0.17 ± 0.080.25 ± 0.20−0.08 ± 0.160.06 ± 0.04>100
    Tezacytabine1.59 ± 0.081.78 ± 0.69−0.19 ± 0.490.63 ± 0.07>100
    Deferoxamine1.00 ± 0.060.92 ± 0.080.08 ± 0.030.17 ± 0.11>100
CTP synthase inhibitors (E.C. 6.3.4.2.)
    CP-C1.97 ± 0.380.91 ± 0.131.06 ± 0.260.64 ± 0.1025
    CPE-C2.47 ± 0.331.21 ± 0.161.26 ± 0.511.43 ± 0.012.5
    3-DU1.41 ± 0.090.48 ± 0.110.94 ± 0.200.13 ± 0.10∼100
    dFdC1.87 ± 0.160.59 ± 0.051.29 ± 0.111.32 ± 0.08Too toxic
OMPDC inhibitors (EC 4.1.1.23)
    6-Azauridine0.25 ± 0.090.61 ± 0.18−0.36 ± 0.160.12 ± 0.05>100
    2-Thio-6-azauridine0.16 ± 0.04−0.02 ± 0.120.19 ± 0.090.12 ± 0.10>100
    PZF1.88 ± 0.050.42 ± 0.031.46 ± 0.081.16 ± 0.213.80
ATC inhibitors (EC 2.1.3.2)
    PALA1.77 ± 0.020.48 ± 0.021.30 ± 0.051.18 ± 0.117.60
Dihydroorotate dehydrogenase inhibitors (E.C. 1.3.3.1)
    Brequinar (NSC-368390)−0.05 ± 0.050.29 ± 0.01−0.34 ± 0.04−0.17 ± 0.09>100
    Dichloroallyl lawsone (NSC-126771)1.27 ± 0.022.13 ± 0.15−0.86 ± 0.17−0.52 ± 0.01>100
Thymidylate synthase inhibitors (E.C. 2.1.1.45)
    2′-Deoxy-5-fluorouridine0.76 ± 0.060.73 ± 0.350.04 ± 0.250.23 ± 0.05>100
    Methotrexate0.18 ± 0.010.07 ± 0.100.11 ± 0.090.15 ± 0.01>100
Controls
    IFN-α-2a1.57 ± 0.260.21 ± 0.211.36 ± 0.37NAb4.5 IU/ml
    Ribavirin1.96 ± 0.280.91 ± 0.121.05 ± 0.290.16 ± 0.10∼100
    2′-C-CH3-A2.32 ± 0.112.96 ± 0.08−0.64 ± 0.182.051.4
    2′-C-CH3-C2.20 ± 0.52−0.02 ± 0.052.21 ± 0.471.010.4
  • a IFN tested at 100 IU/ml; dFdC tested initially at 50 μM; a meaningful EC90 value could not be attributed because of extreme toxicity.

  • b NA, not applicable.