Simeprevir

Simeprevir is accumulated in the liver after uptake into hepatocytes via OATP1B1/3. NS3/4A heterodimeric complex is composed of the cofactor N4A subunit and N3 subunit which contains the proteolytic site. The NS3/4A protease cleaves the HCV polyprotein downstream of the NS3 site, generating non-structural viral proteins NS3, NS4A, NS4B, NS5A and NS5B and subsequently formation of mature proteins. Simeprevir exerts an inhibitory action on HCV polyprotein cleavage via induced-fit binding to an extended S2 subsite located in the NS3 catalytic site. NS3/4A inhibitors usually depend on few interactions located in the substrate binding groove of the viral serine protease, thus are susceptible to resistance and failed treatment from few critical mutations in these sites. At higher concentration above their antiviral half-maximal effective concentration (EC50), simeprevir and other NS3/4A inhibitors also restore interferon (IFN)-signaling pathways that are thought to be disrupted by NS3/4A protease and recover innate immune processes. NS3/4A protease cleaves two essential adaptor proteins that initiate signaling leading to activation of IFN regulatory factor 3 and IFN-α/β synthesis, which are mitochondrial antiviral-signaling proteins (MAVS otherwise known as IPS-1, VISA, or Cardif) and toll/interleukin-1 receptor (TIR)- domain-containing adaptor-inducing IFN-β (TRIF). Blocking the function of these adaptor proteins results in impaired interferon induction. NS3/4A inhibitors recover the proper IFN-signaling pathways.