TABLE 1.
Antiviral and cytotoxicity effects of antimetabolites on HCV replicon-transfected Huh-7 cells
| Compound | log10 RNA reductiona at 100 μM for: |
Corrected HCV RNA |
|||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| HCV | rRNA | log10 reductiona at 100 μM | log10 reduction at 10 μM | EC90, μM | |||||||
| IMPDH inhibitors (EC 1.1.1.205) | |||||||||||
| Mizoribine | 0.29 ± 0.74 | 0.21 ± 0.50 | 0.08 ± 0.82 | −0.14 ± 0.12 | >100 | ||||||
| Tiazofurin | 0.86 ± 0.27 | 0.99 ± 0.35 | −0.13 ± 0.37 | 0.04 ± 0.10 | >100 | ||||||
| Mycophenolic acid | 1.15 ± 0.43 | 1.09 ± 0.28 | 0.07 ± 0.47 | 0.22 ± 0.01 | >100 | ||||||
| C2-MAD | 1.09 ± 0.21 | 1.00 ± 0.15 | 0.08 ± 0.24 | 0.36 ± 0.21 | >100 | ||||||
| Ribonucleotide reductase inhibitors (EC 1.17.4.1; EC 1.17.4.2) | |||||||||||
| Guanazole | 0.25 ± 0.11 | 0.07 ± 0.03 | 0.32 ± 0.08 | 0.05 ± 0.08 | >100 | ||||||
| Hydroxyurea | 0.17 ± 0.08 | 0.25 ± 0.20 | −0.08 ± 0.16 | 0.06 ± 0.04 | >100 | ||||||
| Tezacytabine | 1.59 ± 0.08 | 1.78 ± 0.69 | −0.19 ± 0.49 | 0.63 ± 0.07 | >100 | ||||||
| Deferoxamine | 1.00 ± 0.06 | 0.92 ± 0.08 | 0.08 ± 0.03 | 0.17 ± 0.11 | >100 | ||||||
| CTP synthase inhibitors (E.C. 6.3.4.2.) | |||||||||||
| CP-C | 1.97 ± 0.38 | 0.91 ± 0.13 | 1.06 ± 0.26 | 0.64 ± 0.10 | 25 | ||||||
| CPE-C | 2.47 ± 0.33 | 1.21 ± 0.16 | 1.26 ± 0.51 | 1.43 ± 0.01 | 2.5 | ||||||
| 3-DU | 1.41 ± 0.09 | 0.48 ± 0.11 | 0.94 ± 0.20 | 0.13 ± 0.10 | ∼100 | ||||||
| dFdC | 1.87 ± 0.16 | 0.59 ± 0.05 | 1.29 ± 0.11 | 1.32 ± 0.08 | Too toxic | ||||||
| OMPDC inhibitors (EC 4.1.1.23) | |||||||||||
| 6-Azauridine | 0.25 ± 0.09 | 0.61 ± 0.18 | −0.36 ± 0.16 | 0.12 ± 0.05 | >100 | ||||||
| 2-Thio-6-azauridine | 0.16 ± 0.04 | −0.02 ± 0.12 | 0.19 ± 0.09 | 0.12 ± 0.10 | >100 | ||||||
| PZF | 1.88 ± 0.05 | 0.42 ± 0.03 | 1.46 ± 0.08 | 1.16 ± 0.21 | 3.80 | ||||||
| ATC inhibitors (EC 2.1.3.2) | |||||||||||
| PALA | 1.77 ± 0.02 | 0.48 ± 0.02 | 1.30 ± 0.05 | 1.18 ± 0.11 | 7.60 | ||||||
| Dihydroorotate dehydrogenase inhibitors (E.C. 1.3.3.1) | |||||||||||
| Brequinar (NSC-368390) | −0.05 ± 0.05 | 0.29 ± 0.01 | −0.34 ± 0.04 | −0.17 ± 0.09 | >100 | ||||||
| Dichloroallyl lawsone (NSC-126771) | 1.27 ± 0.02 | 2.13 ± 0.15 | −0.86 ± 0.17 | −0.52 ± 0.01 | >100 | ||||||
| Thymidylate synthase inhibitors (E.C. 2.1.1.45) | |||||||||||
| 2′-Deoxy-5-fluorouridine | 0.76 ± 0.06 | 0.73 ± 0.35 | 0.04 ± 0.25 | 0.23 ± 0.05 | >100 | ||||||
| Methotrexate | 0.18 ± 0.01 | 0.07 ± 0.10 | 0.11 ± 0.09 | 0.15 ± 0.01 | >100 | ||||||
| Controls | |||||||||||
| IFN-α-2a | 1.57 ± 0.26 | 0.21 ± 0.21 | 1.36 ± 0.37 | NAb | 4.5 IU/ml | ||||||
| Ribavirin | 1.96 ± 0.28 | 0.91 ± 0.12 | 1.05 ± 0.29 | 0.16 ± 0.10 | ∼100 | ||||||
| 2′-C-CH3-A | 2.32 ± 0.11 | 2.96 ± 0.08 | −0.64 ± 0.18 | 2.05 | 1.4 | ||||||
| 2′-C-CH3-C | 2.20 ± 0.52 | −0.02 ± 0.05 | 2.21 ± 0.47 | 1.0 | 10.4 | ||||||
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.