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 K_i of 0.36 nM. Moreover, Simeprevir inhibits HCV replication with an EC₅₀ of 7.8 nM. It also has K_is 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 3CL^pro 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.

Reference:

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