Hepatitis C Virus NS3/4A Protease Inhibitors Incorporating Flexible P2 Quinoxalines Target Drug Resistant Viral Variants
Department of Biochemistry and Molecular Pharmacology; Schiffer Lab
Biochemistry | Medicinal Chemistry and Pharmaceutics | Medicinal-Pharmaceutical Chemistry | Molecular Biology | Structural Biology | Therapeutics
A substrate envelope-guided design strategy is reported for improving the resistance profile of HCV NS3/4A protease inhibitors. Analogues of 5172-mcP1P3 were designed by incorporating diverse quinoxalines at the P2 position that predominantly interact with the invariant catalytic triad of the protease. Exploration of structure-activity relationships showed that inhibitors with small hydrophobic substituents at the 3-position of P2 quinoxaline maintain better potency against drug resistant variants, likely due to reduced interactions with residues in the S2 subsite. In contrast, inhibitors with larger groups at this position were highly susceptible to mutations at Arg155, Ala156, and Asp168. Excitingly, several inhibitors exhibited exceptional potency profiles with EC50 values < /=5 nM against major drug resistant HCV variants. These findings support that inhibitors designed to interact with evolutionarily constrained regions of the protease, while avoiding interactions with residues not essential for substrate recognition, are less likely to be susceptible to drug resistance.
DOI of Published Version
J Med Chem. 2017 Jul 13;60(13):5699-5716. doi: 10.1021/acs.jmedchem.7b00426. Epub 2017 Jun 19. Link to article on publisher's site
Journal of medicinal chemistry
Matthew, Ashley N.; Zephyr, Jacqueto; Hill, Caitlin J.; Jahangir, Muhammad; Newton, Alicia; Petropoulos, Christos J.; Huang, Wei; Yilmaz, Nese Kurt; Schiffer, Celia A.; and Ali, Akbar, "Hepatitis C Virus NS3/4A Protease Inhibitors Incorporating Flexible P2 Quinoxalines Target Drug Resistant Viral Variants" (2017). Schiffer Lab Publications. 19.