Nesbuvir

Nesbuvir is a nonnucleoside inhibitor of the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) polymerase. IC50 & Target: EC50: 9 nM (NS3^V170A), 13 nM (NS3^V170A), 15 nM (NS3^K583T), 13 nM (NS5B^I424V)^[1] In Vitro: Replicon cells are treated with 1 mg/mL G418 and combinations of the two compounds. Nesbuvir (HCV-796) is added to 40 or 80 nM (approximately 10 and 20 times the EC₅₀ in a 3-day replicon inhibition assay, respectively) and Boceprevir is added to 400 or 800 nM (approximately 2 and 4 times the EC₅₀, respectively). The EC₅₀s for Nesbuvir and Boceprevir for the parental replicon in the transient expression assay are comparable to those obtained in the 3-day inhibition assay with the stable replicon cells; the EC₅₀ for Nesbuvir in the transient expression assay is 14 nM, whereas it is 5 nM for the stable replicon; and the EC₅₀ for Boceprevir in the transient expression assay is 608 nM, whereas it is 201 nM for the stable replicon^[1]. In Vivo: Among a huge variety of yet characterized nucleoside and non-nucleoside inhibitors (NNI), the benzofurane derivative NNI Nesbuvir (HCV-796) is demonstrated to yield significant antiviral effects in mice with chimeric human livers and in patients infected with HCV. HCV-796 binds to a hydrophobic binding pocket at the “palm” domain of NS5B; however, its mode of inhibition remains to be defined^[2].