Hepatitis C virus NS3 inhibitors: current and future perspectives

Abstract

Currently, hepatitis C virus (HCV) infection is considered a serious health-care problem all over the world. A good number of direct-acting antivirals (DAAs) against HCV infection are in clinical progress including NS3-4A protease inhibitors, RNA-dependent RNA polymerase inhibitors, and NS5A inhibitors as well as host targeted inhibitors. Two NS3-4A protease inhibitors (telaprevir and boceprevir) have been recently approved for the treatment of hepatitis C in combination with standard of care (pegylated interferon plus ribavirin). The new therapy has significantly improved sustained virologic response (SVR); however, the adverse effects associated with this therapy are still the main concern. In addition to the emergence of viral resistance, other targets must be continually developed. One such underdeveloped target is the helicase portion of the HCV NS3 protein. This review article summarizes our current understanding of HCV treatment, particularly with those of NS3 inhibitors.

Figure 1

HCV genome and polyprotein processing. (a) Open arrow, closed arrows, closed circle, and open circles indicated signal peptide peptidase, signal peptidase, NS2 autoprotease, and NS3-4A serine protease cleavage site(s), respectively. (b) This figure was drawn by UCSF Chimera (http://www.cgl.ucsf.edu/chimera/), a software program for visualizing molecules, with the structural data from Protein Data Bank (PDB) ID 3O8R. Each domain of NS3 was color-coded. Both blue and purple represent helicase core domain, and green and yellow indicate C-terminal region and protease domain, respectively. ADP and RNA were drawn in red as ligands.