Quinoxaline-Based Linear HCV NS3/4A Protease Inhibitors Exhibit Potent Activity against Drug Resistant Variants
Authors
Rusere, LinahMatthew, Ashley N.
Lockbaum, Gordon J.
Jahangir, Muhammad
Newton, Alicia
Petropoulos, Christos J.
Huang, Wei
Yilmaz, Nese Kurt
Schiffer, Celia A.
Ali, Akbar
UMass Chan Affiliations
Graduate School of Biomedical Sciences, MD/PhD ProgramSchiffer Lab
Department of Biochemistry and Molecular Pharmacology
Document Type
Journal ArticlePublication Date
2018-05-17Keywords
crystal structuredrug resistance
HCV
NS3/4A protease
protease inhibitor quinoxaline
Biochemistry
Chemistry
Heterocyclic Compounds
Medicinal Chemistry and Pharmaceutics
Medicinal-Pharmaceutical Chemistry
Molecular Biology
Pharmacology
Structural Biology
Metadata
Show full item recordAbstract
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.Source
ACS Med Chem Lett. 2018 May 17;9(7):691-696. doi: 10.1021/acsmedchemlett.8b00150. eCollection 2018 Jul 12. Link to article on publisher's site
DOI
10.1021/acsmedchemlett.8b00150Permanent Link to this Item
http://hdl.handle.net/20.500.14038/48876PubMed ID
30034602Related Resources
ae974a485f413a2113503eed53cd6c53
10.1021/acsmedchemlett.8b00150