. 2010 Feb 22;54(5):1878–1887. doi: 10.1128/AAC.01452-09

TABLE 1.

Effects of NS3 mutations on antiviral activities of several NS3/4A protease inhibitors^a

Mutant	RC (% of that for WT)	TMC435		BILN-2061		ITMN-191		Boceprevir		Telaprevir
Mutant	RC (% of that for WT)	EC₅₀ (nM)	FC	EC₅₀ (nM)	FC	EC₅₀ (nM)	FC	EC₅₀ (nM)	FC	EC₅₀ (nM)	FC
WT	100	11	NA	0.8	NA	0.5	NA	148	NA	150	NA
V36L	56	18	1.7	1.4	1.0	ND	ND	110*	1.6*	300*	3.1*
V36 M	43	20	2.0	2.4	1.2	ND	ND	217	1.8	886	10
V36A	22	34	2.8	1.0	1.1	1.3*	3.1*	1,454	6.8	ND	ND
Q41R	ND	18	1.7	2.3	2.8	ND	ND	ND	ND	ND	ND
F43S	63	83	12	1.0	0.9	5.1*	15*	333	5.2	749	6.1
F43I	ND	562*	89*	0.4*	0.5*	ND	ND	242*	1.1*	ND	ND
F43V	ND	626*	99*	0.4*	0.5*	ND	ND	527*	2.4*	ND	ND
T54A	61	5.9	0.6	0.7	0.6	0.6*	1.3*	268	2.1	1,565	7.5
T54S	ND	5.4	1.2	0.9	1.9	ND	ND	1,106	8.5	ND	ND
Q80R	40	49	6.9	1.4	1.6	4.5	3.5	85	0.5	216	0.6
Q80H	ND	41	3.6	1.2	1.1	1.0*	1.4*	78	0.5	ND	ND
Q80K	98	62	7.7	1.0	0.9	0.9	2.3	94	0.8	147	0.5
Q80G	111	22	1.8	3.0	4.9	3.5	9.8	127	1.2	202	1.2
Q80L	169*	12	2.1	0.8	1.2	ND	ND	133	0.9	ND	ND
R109K	311	11	0.7	1.4	0.7	ND	ND	33*	1.0*	66*	0.8*
S138T	19*	77	4.4	0.5	3.0	3.0	3.4	16	0.1	ND	ND
R155 M	33	3.5	0.4	84	68	3.8*	21*	792	5.7	4,106	14
R155I	ND	6.6*	0.8*	29*	39*	7.0*	20*	5,343*	28*	ND	ND
R155Q	10	21	1.6	248	242	13*	68.*	174	1.4	570	2.5
R155T	7	314	24	685	562	48*	261*	5,463	51	22,663	74
R155K	40	260	30	489	496	135	447	743	4.7	1,470	10
R155G	4	350	20	1,002	811	79*	324*	4,467	20	9,631	20
A156S	71	3.0	0.3	1.7	2.8	ND	ND	525	3.5	3,107	20
A156G	66	206	16	22*	12*	ND	ND	65	2.1	58	0.6
A156T	30	377	44	1,066	1,344	4.8	41*	7,227	65	20,326	105
A156V	18	2,149	177	1,518	2,085	12	63	9,673	75	15,470	112
D168G	ND	42	4.4	35	38	2.2	8.1*	63	0.4	ND	ND
D168N	67*	79	6.6	18	12	ND	ND	101	1.9	147	1.2
D168E	34	302	40	40	65	6.1	75*	69	0.8	113	0.6
D168T	192	4,089	308	520	844	42	227	299	1.1	181	1.0
D168Y	30	6,238	666	2,099	2,488	78	391	193	2.4	187	1.2
D168H	104	5,655	368	215	263	26	133	73	0.7	102	0.7
D168A	90	6,356	594	304	339	31	153	100	0.7	46	0.4
D168V	94	17,917	2,591	1,813	3,213	ND	ND	83	0.5	ND	ND
D168I	36	23,203*	1,807*	20,715*	26,822*	104*	195*	279*	1.1	ND	ND
V170T	ND	52	5.4	4.8	4.6	0.6*	1.1*	210*	1.6*	ND	ND
V170A	30	22*	1.8*	0.8	1.4	0.7*	1.1*	1,546	5.8	ND	ND
F43S + Q80R	ND	1,815*	286*	0.4*	0.6*	ND	ND	1,554*	7.4*	ND	ND
F43S + D168E	ND	3,607	694	5.8	12	ND	ND	417	3.2	ND	ND
Q80K + R155K	66	4,647	364	705	736	309	850	1,077	5.1	2,957	4.6
Q80R + R155K	157	2,853	270	707	772	ND	ND	680*	2.7*	ND	ND
Q80R + D168E	52*	5,902	412	87	103	106	154	62	0.6	ND	ND
Q80H + D168E	ND	1,362	163	52	49	26	40*	20*	0.1*	ND	ND
Q80R + D168A	ND	16,867*	2,655*	1,039*	1,827*	ND	ND	113*	0.5*	ND	ND

EC₅₀s were determined in a transient replicon assay with the wild-type or mutant replicon with single- or multiple-site-directed mutations in a genotype 1b replicon backbone (clone ET) with a luciferase readout. The EC₅₀s presented here were calculated as the medians of the EC₅₀s derived from individual experiments. The replication capacity levels of the mutants are expressed as a percentage relative to that for the wild type. Median values are shown, and values derived from less than three independent experiments are indicated with asterisks. The mutations observed during the selection experiments with TMC435 and the data for replicons with those mutations are labeled in boldface. RC, replication capacity; WT, wild type; FC, median of the fold change in the EC₅₀ for the mutant replicon compared to that for the wild-type replicon determined in each experiment; ND, not determined; NA, not applicable.