Hepatitis C virus (HCV) is a positive-strand RNA virus grouped in the genus Hepacivirus within the family Flaviviridae. HCV is classified into at least 6 genotypes (gt), and its error-prone polymerase leads to more than 50 subtypes. The long open reading frame, which encodes the HCV polyprotein, is processed by host and viral proteases and gives rise to three structural proteins (the capsid protein core and envelope glycoproteins E1 and E2) and seven nonstructural (NS) proteins (p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B). Among them, the NS3 protein is composed of a serine protease and an RNA helicase/nucleoside triphosphatase (NTPase), NS4A serves as a cofactor for NS3 serine protease. The HCV RNA-dependent RNA polymerase (RdRp) has long been a prime target for antiviral development because of its critical role in viral replication and the absence of a mammalian homologous enzyme.

Grazoprevir (also known as MK-5172) is a selective and orally active HCV NS3/4a protease inhibitor.

Meanwhile, Grazoprevir shows a broad activity across genotypes and common resistant variants. In the replicon assay, Grazoprevir potently against genotypes 1a, 1b, 2a, and the R155K and D168Y mutations. In both rat and dog, Grazoprevir demonstrates good plasma and liver exposures, with 24-h liver levels suggestive of once-daily dosing. Among them, in rat, Grazoprevir shows a plasma clearance of 28 mL/min/kg and a plasma half-life of 1.4 h. In addition, when dosed orally at 5 mg/kg, the plasma exposure of Grazoprevir is good with an AUC of 0.7 μM h. Moreover, the liver exposure of the compound is quite good (23 μM at 4 h), and Grazoprevir remains in liver 24 h after a single 5 mg/kg oral dose. Besides, Grazoprevir suppresses viral load in HCV-infected chimpanzees harboring chronic gt1a or gt1b infections.

To sum up, Grazoprevir is a selective and orally active HCV NS3/4a protease inhibitor, has the potential for the hepatitis C research.


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

[2] Steven Harper, et al. ACS Med Chem Lett. 2012 Mar 2;3(4):332-6.