Figure 1.
The chemical structures of NS3/4A protease inhibitors.
The canonical nomenclature for drug moiety positioning is indicated using telaprevir. Telaprevir (black), danoprevir (red), vaniprevir and MK-5172 (blue) are representative of many other protease inhibitors in development. Telaprevir, recently approved for clinical use, is an acyclic ketoamide inhibitor that forms a reversible, covalent bond with the protease. Danoprevir, currently in phase II clinical trials, is a non-covalent acylsulfonamide inhibitor with a P1–P3 macrocycle. Vaniprevir and MK-5172 are also non-covalent acylsulfonamide inhibitors, but contain P2–P4 macrocycles. Vaniprevir and MK-5172 differ in the construction of their P2 moieties: vaniprevir contains a carbamate linkage between the P2 proline and the isoindoline moiety, whereas MK-5172 contains a shorter ether linkage between its P2 proline and the quinoxaline moiety.
Table 1.
Drug susceptibilities against wild-type and resistant HCV clones and inhibitory activities against NS3/4A proteases.
Table 2.
X-ray data collection and crystallographic refinement statistics.
Figure 2.
The binding conformations of telaprevir, danoprevir, vaniprevir and MK-5172.
Surface representations of the wild-type protease in complex with (A) telaprevir, (B) danoprevir, (C) vaniprevir, and (D) MK-5172. The catalytic triad is shown in yellow and the R155, A156 and D168 side chains are highlighted in light-blue, pale-green and red, respectively.
Figure 3.
Stereo view of the telaprevir complexes.
(A) Telaprevir bound to the wild-type protease with the substrate envelope in blue. Intra- and inter-molecular hydrogen bond interactions are marked as red and grey dashed lines. Telaprevir is also shown bound to the drug-resistant variants (B) R155K, (C) D168A and (D) A156T with the transparent coordinates representing the wild-type structure to better highlight the molecular changes of each mutation. In all cases, catalytic residues are depicted in yellow, the P2 subsite in pink, and the drug molecules in orange.
Figure 4.
Stereo view of the danoprevir complexes.
(A) Danoprevir bound to the wild-type protease with the substrate envelope in blue. Intra- and inter-molecular hydrogen bond interactions are marked as red and grey dashed lines. Danoprevir is also shown bound to the drug-resistant variants (B) R155K, (C) D168A and (D) A156T with the transparent coordinates representing the wild-type structure to better highlight the molecular changes of each mutation. In all cases, catalytic residues are depicted in yellow, the P2 subsite in pink, and the drug molecules in orange.
Figure 5.
Stereo view of the vaniprevir complexes.
(A) Vaniprevir bound to the wild-type protease with the substrate envelope in blue. Intra- and inter-molecular hydrogen bond interactions are marked as red and grey dashed lines. Vaniprevir is shown bound to the drug-resistant variants (B) R155K, (C) D168A and (D) A156T with the transparent coordinates representing the wild-type structure to better highlight the molecular changes of each mutation. In all cases, catalytic residues are depicted in yellow, the P2 subsite in pink, and the drug molecules in orange.
Figure 6.
Stereo view of the MK-5172 complexes.
(A) MK-5172 bound to the wild-type protease with the substrate envelope in blue. Intra- and inter-molecular hydrogen bond interactions are marked as red and grey dashed lines. MK-5172 is shown bound to the drug-resistant variants (B) R155K, (C) D168A and (D) A156T with the transparent coordinates representing the wild-type structure to better highlight the molecular changes of each mutation. In all cases, catalytic residues are depicted in yellow, the P2 subsite in pink, and the drug molecules in orange.
Figure 7.
Drug interactions with wild-type and mutant complexes by residue.
The Van der Waals contact energy indexes for the wild-type protease and mutant variants R155K, D168A and A156T are shown by protease residue for (A) telaprevir, (B) danoprevir, (C) vaniprevir and (D) MK-5172.