Grazoprevir is a Selective Inhibitor of Hepatitis C Virus NS3/4a Protease

Hepatitis C virus (HCV) is a member of the Flaviviridae family of viruses in the Hepacivirus genus. Meanwhile, HCV NS3-4A serine protease is a complex composed of NS3 and its cofactor NS4A. HCV infection is associated with chronic liver disease, including hepatic steatosis, fibrosis, cirrhosis, and hepatocellular carcinoma. The NS3-4A serine protease of HCV has been one of the most attractive targets for developing specific antiviral agents against HCV. It harbours serine protease as well as NTPase/RNA helicase activities and is essential for viral polyprotein processing, RNA replication and virion formation. HCV NS3/4a protease inhibitors are useful therapeutic agents against chronic HCV infection.

Grazoprevir (also known as MK-5172) is a selective inhibitor of HCV NS3/4a protease with broad activity across genotypes and resistant variants. And this compound shows subnanomolar to low-nanomolar EC50s against genotypes 1a, 1b, and 2a. In addition, in replicon selections, Grazoprevir exerts high selective pressure, which yielded few resistant colonies. Furthermore, phenotypic analysis shows that Grazoprevir maintained its effectiveness in the genetic diversity panel of genotype 1a and 1b sequences. Preclinical pharmacokinetic shows that Grazoprevir has good plasma and liver exposures, and shows a moderate half-life in both rat and dog. Moreover, oral administration of a moderate dose of MK-5172 displays highly efficacious against chronic-HCV-infected chimpanzees. Besides, recent studies have found that Grazoprevir also has the activity of inhibiting SARS-CoV-2 3CLpro.

To sum up, Grazoprevir is a selective HCV NS3/4a protease inhibitor, with broad activity across genotypes and resistant variants.


[1] Vincenzo Summa, et al. Antimicrob Agents Chemother. 2012 Aug;56(8):4161-7.

[2] Qi Sun, et al. Signal Transduct Target Ther. 2021 May 29;6(1):212.