HCV NS5A Inhibitors: The Devil Is in the Details Menashe Elazar  Gastroenterology  Volume 147, Issue 2, Pages 273-277 (August 2014) DOI: 10.1053/j.gastro.2014.06.021 Copyright © 2014 AGA Institute Terms and Conditions

Figure 1 HCV life cycle and the potential sites of NS5A inhibitor action. (A) The HCV life cycle. Upon entry (i), the viral genome uncoats (ii) and is translated to generate the viral proteins (iii). The non-structural proteins 4B and 5A modify host membranes to form the sites of HCV replication—termed the membranous webs (iv)--upon which the HCV replication complex is assembled and RNA is synthesized. The HCV RNA and capsid protein then assemble and enter into the ER-lumen along with membranes decorated with the envelope proteins (v). The virus is then transported via the secretory pathway to exit the cell (vi). (B) Possible sites of NS5A inhibitor action. NS5A inhibitors act on newly formed RNA replication complexes (vii) but not on preformed ones (viii). The synthesized RNA is then transported from the replication complex via an unknown mechanism, possibly involving NS5A (ix), to within close proximity of lipid droplets and the RNA assembles with the capsid protein in close proximity to lipid droplets (x). The assembly progresses by association of the RNA-capsid proteins complex with envelope proteins within the ER-lumen. Rapid inhibition of assembly by NS5A inhibitors (as demonstrated by McGivern et al.) is hypothesized to be the result of targeting (ix) and (x), and may also be mediated by negative feedback (xi) triggered by inhibition of RNA replication with resulting diversion of RNA templates towards replication as opposed to assembly. Gastroenterology 2014 147, 273-277DOI: (10.1053/j.gastro.2014.06.021) Copyright © 2014 AGA Institute Terms and Conditions