Simeprevir is an Orally Active HCV NS3/4A Protease Inhibitor

Hepatitis C is a blood-borne infection that can ultimately result in severe liver diseases, including fibrosis, cirrhosis, and hepatocellular carcinoma. The chronic nature of the disease and the significant possibility of long-term liver damage have led to the current global health burden. There are 180 million people has hepatitis C, of whom 130 million are chronic hepatitis C virus (HCV) carriers. HCV NS3 is an essential, bifunctional, multidomain protein that possesses protease and RNA helicase activities. NS3/4A, the viral enzyme target of Simeprevir, is a serine protease with a trypsin-like fold that comprises the 181-residue N-terminal protease domain of NS3 and the 54-residue NS4A cofactor. The association of the NS4A cofactor with the NS3 protease domain is required for enzymatic function, stability, and anchoring to the endoplasmic reticulum. The NS3/4A protease is responsible for cleavage of the HCV polyprotein at the junctions between NS3/NS4A, NS4A/NS4B, NS4B/NS5A, and NS5A/NS5B.

Simeprevirs is an oral and potent HCV NS3/4A protease inhibitor.

Simeprevir is a competitive macrocyclic inhibitor of the HCV NS3/4A protease with a Ki of 0.36 nM. Moreover, Simeprevir inhibits HCV replication with an EC50 of 7.8 nM. It also has Kis of 0.4 nM and 0.5 nM against genotype 1a and 1b enzymes, respectively. It also has an EC50 of 8 nM in a genotype 1b replicon cell line. Furthermore, Simeprevir with IFN-α and an HCV NS5B polymerase inhibitor results in synergistic activity, and that the use of Simeprevir with ribavirin results in additive activity. In addition, Simeprevir inhibits SARS-CoV-2 3CLpro activity. Simeprevir also potently reduces SARS-CoV-2 viral load by multiple orders of magnitude and synergizes with remdesivir in vitro.

In summary, Simeprevir is a potent inhibitor of the NS3/4A serine protease of HCV. It also has the potential for the research of COVID-19.


Raboisson P, et al. Bioorg Med Chem Lett. 2008 Sep 1;18(17):4853-8.; Lenz O, et al. 2010;54(5):1878-1887.