Table 4.
Mutations and antiviral phenotype of replicons obtained following culturing in the presence of A-782759a using various selection protocols
| Antiviral pressure (fold EC50) | Fold increaseb compared to WT | EC50 ± SDb (μM) | NS5B mutation(s) (aa 1-591)c | Critical phased |
|---|---|---|---|---|
| 1 | 4 | 0.31 ± 0.05 | NP | N |
| 2 | 5 | 0.38 ± 0.03 | S556S/G | N |
| 5 | 11 | 0.86 ± 0.6 | C445C/F, S556S/G, W571P | N |
| 25 | 120 | 9 ± 0.7 | S556S/G, W571P | N |
| 125 | 293 | 22 ± 10 | G554G/D, Y555Y/C, S556S/G | Y |
| 2-5 | 13 | 0.99 ± 0.3 | A73A/S, C445C/F, Y555C/R/Y/H, S556S/G | N |
| 2-25 | 67 | 5 ± 1 | A73A/S, S556S/G | N |
| 2-125 | 240 | 18 ± 7 | A73A/S, M414 M/T, G554G/D, S556S/G | N |
| 5-25 | 80 | 6 ± 0.5 | A73A/S, V122V/L, L126L/V, D135D/G, C445C/F, S556S/G | N |
| 5-125 | >440 | >33 | L47L/M, A73A/S, C316C/Y, M414 M/T, C445C/F, T520T/I, S556S/G | Y |
| 25-125 | 200 | 15 ± 1 | A73A/S, C445C/F, S476S/N, S556S/G | N |
| 2-5-25 | 107 | 8 ± 0.6 | A73A/S, M414 M/T, G554G/D, Y555Y/C, S556S/G | N |
| 2-5-125 | 293 | 22 ± 2 | A73A/S, C311C/Y, C316C/Y, M414 M/T, Y555Y/C, S556S/G | Y |
| 2-25-125 | >440 | >33 | A73A/S, V108V/A, D135D/G, M414 M/T, C445C/F, Y452Y/H, G554G/D, S556S/G, W571P | N |
| 5-25-125 | >440 | >33 | L47L/M, A73A/S, A207A/G, C316C/Y, C445C/F, S556S/G, W571P | N |
| 2-5-25-125 | >440 | >33 | A73A/S, C316C/Y, C445C/F, I447I/M, G554G/D, S556S/G | N |
a
EC50, 0.075 ± 0.01 μM; CC50 > 33 μM.
b
Data are mean values for ≥2 independent determinations of the antiviral phenotype.
c
Major resistance mutations are indicated in boldface. aa, amino acids; NP, none present.
d
Y, yes; N, no.