Liangjun Lu, Rakesh Tripathi, Keith F McDaniel, Timothy Middleton, Jun Ma, Tatyana Dekhtyar, Michelle Irvin, Thomas Reisch, Yat Sun Or, Dale Kempf, Gretja Schnell, Guoqiang Wang, Christine Collins, Teresa I Ng, Preethi Krishnan, Li-Juan Jiang, Todd A Hopkins, Tami Pilot-Matias, Jill Beyer, Ron Pithawalla
Glecaprevir (formerly ABT-493) is a novel hepatitis C virus (HCV) NS3/4A protease inhibitor (PI) with pan-genotypic activity. It inhibited the enzymatic activity of purified NS3/4A proteases from HCV genotypes 1 - 6 in vitro (IC50 = 3.5 - 11.3 nM) and the replication of stable HCV subgenomic replicons containing proteases from genotypes 1 - 6 (EC50 = 0.21 - 4.6 nM). Glecaprevir had a median EC50 value of 0.30 nM (range 0.05 - 3.8 nM) for HCV replicons containing proteases from 40 HCV genotype 1 - 5 samples. Importantly, glecaprevir is active against the protease from genotype 3, the most difficult-to-treat HCV genotype, in both enzymatic and replicon assays with comparable activity against other HCV genotypes. In drug-resistant colony selection studies, glecaprevir generally selected substitutions at NS3 amino acid position A156 in replicons containing proteases from genotypes 1a, 1b, 2a, 2b, 3a, and 4a, and substitutions at position D/Q168 in replicons containing proteases from genotypes 3a, 5a and 6a. Although substitutions A156T and A156V in NS3 of genotype 1 reduced susceptibility to glecaprevir, they demonstrated low replication efficiency in vitro Glecaprevir is active against most of the common NS3 amino acid substitutions that are associated with reduced susceptibility to currently approved HCV PIs, including those at positions 155 and 168. Combination of glecaprevir with HCV inhibitors with other mechanisms of action resulted in additive or synergistic antiviral activity. In summary, glecaprevir is a next-generation HCV PI with potent pan-genotypic activity and a high barrier to the development of resistance.