Grazoprevir is a potent pan-genotype, macrocyclic inhibitor of hepatitis C virus (HCV) NS3/4A protease and was developed for treating chronic HCV infection. In HCV genotype (GT) 1a, grazoprevir maintains potent activity against a majority of NS3 resistance-associated amino acid substitutions including the highly prevalent and naturally-occurring Q80K polymorphism that impacts simeprevir, another NS3/4A protease inhibitor. The basis for an unexpected difference in the clinical impact of some NS3 substitutions was investigated. Phenotypic analysis of resistance-associated substitutions identified in NS3 from GT1a-infected patients who failed therapy with grazoprevir (in combination with elbasvir, an inhibitor of HCV NS5A protein) showed that positions 56, 156, and 168 in NS3 were most impactful because they diminished protein-inhibitor interactions. While an amino acid substitution from aspartic acid (D) to alanine (A) at position 168 (D168A) reduced the potency of grazoprevir, its combination with R155K unexpectedly nullified this effect. Molecular dynamics and free-energy surface studies indicated that D168 is important in anchoring R155 for ligand binding, but is not critical for K155 because of the inherent flexibility of its side-chain. Moreover, modeling studies supported a strong direct cation-heterocycle interaction between the K155 side-chain of the double substitution, R155K_D168A, and the lone pair on the pyridine in grazoprevir. This unique interaction provides a structural basis for grazoprevir's higher potency than simeprevir, an NS3/4A protease inhibitor, to which the double substitution confers a significant reduction in potency. Our findings are consistent with the detection of R155K_D168A in NS3 from virologic failures treated with simeprevir but not grazoprevir.
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