Isothiazoles as active-site inhibitors of HCV NS5B polymerase

Isothiazole analogs were discovered as a novel class of active-site inhibitors of HCV NS5B polymerase. The best compound has an IC50 of 200 nM and EC50 of 100 nM, which is a significant improvement over the starting inhibitor (1). The X-ray complex structure of 1 with HCV NS5B was obtained at a resolution of 2.2 Å, revealing that the inhibitor is covalently linked with Cys 366 of the ‘primer-grip’. Furthermore, it makes considerable contacts with the C-terminus, β-loop, and more importantly, to the active-site of the enzyme. The uniqueness of this binding mode offers a new insight for the rational design of novel inhibitors for HCV NS5B polymerase.

Graphical abstractA novel series of potent active-site inhibitors for HCV NS5B polymerase was identified, and the corresponding X-ray structural study was described.Figure optionsDownload full-size imageDownload as PowerPoint slide