6CVY

Crystal structure of HCV NS3/4A WT protease in complex with AJ-21 (MK-5172 linear analogue)

Summary for 6CVY

• Entry DOI: 10.2210/pdb6cvy/pdb
• Descriptor: NS3 protease, ZINC ION, SULFATE ION, ... (6 entities in total)
• Functional Keywords: ns3/4a protease, hepatitis c virus, drug resistance, protease inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Hepacivirus C
• Total number of polymer chains: 1
• Total formula weight: 22558.22

Authors

Matthew, A.N.,Schiffer, C.A. (deposition date: 2018-03-29, release date: 2018-08-08, Last modification date: 2023-10-04)

Primary citation

Rusere, L.N.,Matthew, A.N.,Lockbaum, G.J.,Jahangir, M.,Newton, A.,Petropoulos, C.J.,Huang, W.,Kurt Yilmaz, N.,Schiffer, C.A.,Ali, A.
Quinoxaline-Based Linear HCV NS3/4A Protease Inhibitors Exhibit Potent Activity against Drug Resistant Variants.
ACS Med Chem Lett, 9:691-696, 2018

PubMed Abstract: A series of linear HCV NS3/4A protease inhibitors was designed by eliminating the P2-P4 macrocyclic linker in grazoprevir, which, in addition to conferring conformational flexibility, allowed structure-activity relationship (SAR) exploration of diverse quinoxalines at the P2 position. Biochemical and replicon data indicated preference for small hydrophobic groups at the 3-position of P2 quinoxaline for maintaining potency against resistant variants R155K, A156T, and D168A/V. The linear inhibitors, though generally less potent than the corresponding macrocyclic analogues, were relatively easier to synthesize and less susceptible to drug resistance. Three inhibitor cocrystal structures bound to wild-type NS3/4A protease revealed a conformation with subtle changes in the binding of P2 quinoxaline, depending on the 3-position substituent, likely impacting both inhibitor potency and resistance profile. The SAR and structural analysis highlight inhibitor features that strengthen interactions of the P2 moiety with the catalytic triad residues, providing valuable insights to improve potency against resistant variants.

PubMed: 30034602
DOI: 10.1021/acsmedchemlett.8b00150

Experimental method

X-RAY DIFFRACTION (1.798 Å)