Table 5.

Cross-resistance studies of PSI-352938 using replicon mutants resistant to nucleoside/nucleotide analogs and nonnucleoside inhibitors

NS5B resistance mutation	HCV inhibitor	EC90 (μM)a		EC90 fold changeb
		WT replicon	Mutant replicon
S282T	R1479	22.35 ± 4.58	12.53 ± 3.78	0.56
	INX-08189	0.018 ± 0.001	0.11 ± 0.004	6.11
	PSI-352938	1.38 ± 0.67	1.61 ± 0.19	1.17
S96T/N142T	R1479	15.76 ± 3.67	74.12 ± 12.12	4.70
	INX-08189	0.0054 ± 0.0036	0.0059 ± 0.0027	1.09
	PSI-352938	0.59 ± 0.34	0.53 ± 0.28	0.89
C316Y	HCV-796	0.026 ± 0.017	1.92 ± 0.77	73.85
	PSI-352938	0.88 ± 0.24	0.95 ± 0.30	1.08
M414T	Benzothiadiazine compound	1.23 ± 0.55	28.39 ± 13.70	23.08
	PSI-352938	0.88 ± 0.24	0.93 ± 0.38	1.06
M423T	Thiophene compound	3.65 ± 0.21	69.52 ± 9.24	19.05
	PSI-352938	0.88 ± 0.24	0.76 ± 0.20	0.86
P495L	2-Phenol indole compound	1.17 ± 0.46	60.75 ± 19.90	51.92
	PSI-352938	0.88 ± 0.24	0.65 ± 0.19	0.74

^aThe wild-type (WT) and S282T replicon cells were derived from the clone A cell line. EC₉₀s were determined using the RT-PCR assay. The S96T/N142T, C316Y, M414T, M423T, and P495L replicons were derived from the ET construct transfected into Lunet cells. EC₉₀s were determined using the Firefly luciferase assay and compared to those generated from the wild-type ET-Lunet replicon cells. All values are reported as the means ± standard deviations from at least three independent experiments performed in duplicate.

^bFold change in EC₉₀ was calculated by normalizing the EC₉₀ value for the test compound in the mutant replicon cells with that of the wild type.