Each of them has demonstrated potent anti-HCV activity in 3-day MK-2206 order monotherapy studies in HCV genotype (GT) 1 infected individuals with and without cirrhosis. In this

report, we present results of the characterization of their antiviral activities in the HCV replicon system as individual DAAs or in combination with each other. Methods: The antiviral potency and resistance profile of ABT-530 and ABT-493 were evaluated in assays using subgenomic HCV replicon cell lines expressing NS5A or NS3, respectively, from all major HCV GTs. The genetic barriers to resistance of these DAAs in HCV replicon cells were measured by colony selection assays. The antiviral activity of the combination of ABT-530 and ABT-493 was studied using multiple assays: (1) 3-day checkerboard study detected by reporter activity, (2) 3-week passage of the replicon cells in the presence of inhibitors as monitored by HCV RNA copy number, and (3) resistant colony selection to determine the number c-Met inhibitor of resistant colonies that survived drug selection. Results: ABT-530 demonstrated pangenotypic potency, high genetic barrier to resistance,

and activity against common viral variants that confer resistance to other NS5A inhibitors. ABT-493 demonstrated potent activity

against all major HCV GTs, and activity against the major resistant variants selected by most PIs currently marketed or in clinical development. Importantly, ABT-493 demonstrated additive to synergistic activity in combination with ABT-530, and their combination reduced HCV RNA copy number more 上海皓元医药股份有限公司 rapidly and to a greater magnitude than each of the individual DAAs. In a resistant colony selection assay, no resistant colonies were selected with the combination of ABT-530 and ABT-493 at concentrations of 10-fold above their respective EC50 values. Conclusions: Both ABT-530 and ABT-493 demonstrated potent antiviral activity against all major HCV GTs in vitro. Additive or synergistic antiviral activity and a high barrier to resistance were observed when HCV replicon cells were treated by these two DAAs in combination. These results, together with the potent antiviral activity of ABT-530 and ABT-493 observed in 3-day monotherapy studies in HCV GT1 infected individuals, support further clinical development of these DAAs in combination for the treatment of chronic HCV infection.