Novel peptidyl α-aminoalkylphosphonates as inhibitors of hepatitis C virus NS3/4A protease

Herein, we describe the synthesis and application of novel phosphonic inhibitors designed to target the NS3/4A protease, which is crucial for the life cycle of hepatitis C virus. We examined the inhibitory potency of our synthesized compounds against two genotypes (la and lb) of NS3/4A protease and four mutant strains of HCV. The most potent inhibitors displayed k(2)/K-I values of 79 850 M(-1)s(-1) and 60 850 M(-1)s(-1) against genotype la and lb protease, respectively. Further in vitro evaluation of the most potent inhibitors revealed that vastly reduced HCV replication. Cellular toxicity, plasma stability, reactivity with selected human proteases as well the stability of inhibitor-protease complex and its intracellular availability are also discussed. (C) 2017 Elsevier B.V. All rights reserved.