HCV NS3/4A Protease Inhibitors

Hepatitis C virus (HCV) is a leading cause of chronic liver disease, cirrhosis, liver failure, and hepatocellular carcinoma. The HCV NS3/4A protease is a major target for developing direct-acting antivirals for the treatment of HCV infections, but the genetic diversity of HCV has presented a challenge in developing effective pan-genotypic therapies. We have closely worked with Dr. Celia Schiffer and her team to develop a substrate envelope model for HCV NS3/4A protease. We evaluated the role of macrocyclic linker in the susceptibility of inhibitors to drug resistance. Through extensive structural studies of wild-type NS3/4A protease and drug-resistant variants in complex with inhibitors in clinical development, we defined the molecular basis of drug resistance against NS3/4A protease inhibitors. These studies provided a detailed understanding of the molecular mechanisms underlying drug resistance in HCV NS3/4A protease. Based on the structural insights, we rationally designed new NS3/4A protease inhibitors that retain low nM antiviral activity against major drug-resistant variants of HCV. These studies demonstrated that combining the substrate envelope model with optimal conformational flexibility provides a rational approach to design HCV NS3/4A protease inhibitors with improved resistance profiles.

Recent Publications:

Nageswara Rao. D.; Zephyr, J.; Henes, M.; Chan, E. T.; Matthew, A. N.; Hedger, A. K.; Conway, H. L.; Saeed, M.; Newton, A.; Petropoulos, C. J.; Huang, W.; Yilmaz, N. K.; Schiffer, C. A.; Ali, A. Discovery of Quinoxaline-Based P1–P3 Macrocyclic NS3/4A Protease Inhibitors with Potent Activity against Drug-Resistant HCV Variants. Med. Chem. 2021, 64, 11972–11989.

Matthew, A. N.; Zephyr, J.; Hill, C. J.; Jahangir, M.; Newton, A.; Petropoulos, C. J.; Huang, W.; Yilmaz, N. K.; Schiffer, C. A.; Ali, A. Hepatitis C Virus NS3/4A Protease Inhibitors Incorporating Flexible P2 Quinoxalines Target Drug Resistant Viral Variants. Med. Chem. 2017, 60, 5699–5716.