Table 1.
Replicon EC50 of telaprevir against NS3 protease variantsa
| Variant | EC50 ± SD (μM) | Fold change ± SD |
|---|---|---|
| Frequently observed in telaprevir studies | ||
| G1b replicon (48-h assay) | ||
| WT | 0.482 ± 0.122 | 1.0 ± 0.3 |
| V36A | 3.57 ± 1.05 | 7.4 ± 2.2 |
| V36M | 3.38 ± 0.78 | 7.0 ± 1.6 |
| T54A | 3.04 ± 0.82 | 6.3 ± 1.7 |
| T54S | 2.02 ± 0.19 | 4.2 ± 0.4 |
| R155K | 3.59 ± 0.28 | 7.4 ± 0.6 |
| R155T | 9.60 ± 0.87 | 20 ± 2 |
| A156Sb | 4.65 | 9.6 |
| A156Tc | >30 | >62 |
| V36M + R155K | ∼31 | ∼64 |
| G1a replicon (96-h assay) | ||
| WT | 0.961 ± 0.132 | 1.0 ± 0.1 |
| V36A | 7.25 ± 0.41 | 7.5 ± 0.4 |
| V36M | 6.55 ± 0.56 | 6.8 ± 0.6 |
| R155K | 5.66 ± 1.86 | 5.9 ± 1.9 |
| A156S | 21.5 ± 2.7 | 22 ± 3 |
| V36M + R155K | >25 | >26 |
| Rarely observed in telaprevir studies | ||
| G1b replicon (48-h assay) | ||
| WT | 0.482 ± 0.122 | 1.0 ± 0.3 |
| V36C | 3.78 ± 0.48 | 7.8 ± 1.0 |
| V36G | 5.43 ± 0.21 | 11 ± 0.4 |
| V36L | 1.06 ± 0.20 | 2.2 ± 0.4 |
| R155G | 3.58 ± 0.24 | 7.4 ± 0.5 |
| R155I | 11.6 ± 2.5 | 24 ± 5 |
| R155M | 2.68 ± 0.21 | 5.6 ± 0.4 |
| R155S | 1.97 ± 0.21 | 4.1 ± 0.4 |
| A156F | >30 | >62 |
| A156Vc | >30 | >62 |
| V36A + T54A | 9.73 ± 1.41 | 20 ± 3 |
| V36A + R155K | ∼20 | ∼41 |
| V36A + R155T | >30 | >62 |
| V36L + R155K | 10.3 ± 0.5 | 21 ± 1 |
| V36M + R155T | >30 | >62 |
| V36A + A156T | >30 | >62 |
| V36M + A156T | >30 | >62 |
| T54S + R155K | 10.6 ± 0.2 | 22 ± 0.4 |
| T54A + A156S | >30 | >62 |
| T54S + A156S | >30 | >62 |
| T54S + A156T | >30 | >62 |
| R155T + D168N | 11.3 ± 0.3 | 24 ± 1 |
| V36M + T54S + R155K | >30 | >62 |
| G1b replicon (96-h assay) | ||
| WT | 0.269 ± 0.096 | 1.0 ± 0.4 |
| V36I | 0.0853 ± 0.0059 | 0.3 ± 0.02 |
| V151A | 0.230 ± 0.046 | 0.9 ± 0.2 |
| A156N | >25 | >93 |
| G1a replicon (96-h assay) | ||
| WT | 0.961 ± 0.132 | 1.0 ± 0.1 |
| I132V | 1.68 ± 0.66 | 1.8 ± 0.7 |
| Resistant to other HCV protease inhibitors | ||
| G1b replicon (48-h assay) | ||
| WT | 0.482 ± 0.122 | 1.0 ± 0.3 |
| Q41R | 0.720 ± 0.090 | 1.5 ± 0.2 |
| V55A | 1.03 ± 0.11 | 2.1 ± 0.2 |
| Q80R | 0.250 ± 0.020 | 0.5 ± 0.04 |
| R109K | 0.390 ± 0.110 | 0.8 ± 0.2 |
| D168Ab | 0.193 | 0.4 |
| D168N | 0.306 ± 0.042 | 0.6 ± 0.1 |
| D168Vb | 0.163 | 0.3 |
| V170A | 1.25 ± 0.28 | 2.6 ± 0.6 |
| G1a replicon (96-h assay) | ||
| WT | 0.961 ± 0.132 | 1.0 ± 0.1 |
| D168N | 0.910 ± 0.004 | 0.9 ± 0.004 |
The mean EC50 and SD were derived from 8 to 15 and 3 to 5 individual experiments for the WT and variant replicons, respectively. The mean fold change was determined by dividing the mean EC50 of a given variant replicon by that of the WT replicon. The SD of the fold change was determined by dividing the SD of the EC50 of a given variant replicon by the mean EC50 of the WT replicon. “>” denotes that the EC50 or fold change was greater the value presented; the actual value could not be determined since no significant reduction of HCV RNA level was observed at the maximum concentration of telaprevir used (30 μM for the G1b 48-h assay and 25 μM for the G1a or G1b 96-h assays). “∼” denotes that the EC50 or fold change was estimated from a 40% or greater reduction of the HCV RNA level; the actual value could not be determined due to the reduction of HCV RNA not being sufficient.
Data published previously (38).
Data published previously (40).