Table 5.
Susceptibility of 1a replicon variants to BMS-790052a
| Replicon variant | Replication level | Transient assay |
Cell line |
||
|---|---|---|---|---|---|
| EC50 (nM) | FR | EC50 (nM) | FR | ||
| 1a wt | 100 | 0.006 ± 0.004 | 1.0 | 0.022 ± 0.002 | 1.0 |
| M28T | 31 ± 23 | 4.1 ± 0.4 | 683 | 12.4 ± 5.2 | 564 |
| Q30D | 171 ± 134 | >2,000 | >333,333 | >2,000 | >90,909 |
| Q30E | 130 ± 56 | 149.6 ± 89.1 | 24,933 | 259.1 ± 38.0 | 11,777 |
| Q30G | 54 ± 22 | 51.0 ± 14.9 | 8,500 | 45.2 ± 22.1 | 2,055 |
| Q30H | 75 ± 31 | 8.7 ± 1.9 | 1,450 | 8.8 ± 0.0 | 400 |
| Q30K | 19 ± 9 | 145.9 ± 70.5 | 24,317 | 82.1 ± 9.7 | 3,732 |
| Q30L | 37 ± 11 | 0.022 ± 0.004 | 3.7 | 0.079 ± 0.0 | 3.6 |
| Q30P | 114 ± 19 | 0.009 ± 0.0009 | 1.5 | ND | ND |
| Q30R | 41 ± 16 | 7.4 ± 1.1 | 1,233 | ND | ND |
| L31M | 55 ± 15 | 2.1 ± 0.6 | 350 | ND | ND |
| L31V | 117 ± 29 | 20.1 ± 6.0 | 3,350 | 55.1 ± 19.0 | 2,505 |
| L31P/Q/R | No replication | ND | N,D | ND | ND |
| P32L | 18 ± 5 | 1.4 ± 0.2 | 233 | ND | ND |
| H58D | 92 ± 9 | 2.9 ± 0.4 | 483 | ND | ND |
| Y93C | 11 ± 7 | 11.1 ± 4.1 | 1,850 | ND | ND |
| Y93H | 18 ± 11 | 32.2 ± 9.4 | 5,367 | 52.3 ± 20.0 | 2,377 |
| Y93N | 13 ± 8 | 282.1 ± 64.7 | 47,017 | 354.2 ± 119.1 | 16,100 |
| M28T/Q30Rb | 76 ± 23 | 356.4 ± 12.0 | 59,400 | 301.0 ± 94.3 | 13,681 |
| M28T/Y93H | Poor replication | ND | ND | 365.7 ± 55.0 | 16,623 |
| Q30E/Y93H | 6 ± 1 | 403.6 ± 61.6 | 67,267 | 499.9 ± NA | 22,723 |
| Q30H/Y93C | ND | ND | ND | ND | ND |
| Q30H/Y93H | 20 ± 6 | 553.3 ± 207.4 | 92,217 | 393.6 ± NA | 17,891 |
| Q30K/Y93H | ND | ND | ND | ND | ND |
| Q30R/H58D | 60 ± 12 | 2,515.6 ± 61.7 | 419,267 | >2,000 | >90,909 |
| Q30R/Y93H | 6 ± 1 | 340.9 ± 40.8 | 56,817 | 280.5 ± 76.0 | 12,750 |
a
Replication level, mean ± standard deviation relative to the wild type determined from transient assays with the indicated replicons (n ≥ 3). EC50, mean ± standard deviation (n ≥ 3); 1a wt, genotype 1a wild-type replicon; FR, fold resistance; ND, not determined.
b
Detected in cells treated for 3 days at 500 nM BMS-790052.