New therapies on the horizon for hepatitis C Raffaele De Francesco, PhD, Charles M. Rice, PhD  Clinics in Liver Disease  Volume 7, Issue 1, Pages 211-242 (February 2003) DOI: 10.1016/S1089-3261(02)00069-7

Fig. 1 HCV lifecycle. Sequential stages in the HCV replication cycle are summarized, beginning with virus binding to the host cell (hepatocyte) surface. Though each of these steps provides an opportunity for therapeutic intervention, validated assays for inhibitor screening and evaluation have been developed for only a subset (translation, polyprotein processing, and RNA replication). Clinics in Liver Disease 2003 7, 211-242DOI: (10.1016/S1089-3261(02)00069-7)

Fig. 2 Genetic organization and processing of HCV polyprotein Arrows indicate cleavage by host- and HCV-encoded proteinases as indicated. The black bar indicates portion of the E1 signal sequence removed from C by SPP cleavage. Diamonds in the E1 and E2 region indicate glycosylation of the envelope proteins E1 and E2. Abbreviations: C, capsid; E, envelope; F, frameshift protein; NS, nonstructural; SPP, signal peptide peptidase). Clinics in Liver Disease 2003 7, 211-242DOI: (10.1016/S1089-3261(02)00069-7)

Fig. 3 Conserved RNA elements in HCV genome RNA. Schematic of the 9.6 kb HCV genome with the conserved RNA elements in the 5′ NTR, the NS5B coding region, and the 3′ NTR highlighted. The 5′ NTR, in particular the IRES, has received the most attention as a potential antiviral target. Clinics in Liver Disease 2003 7, 211-242DOI: (10.1016/S1089-3261(02)00069-7)

Fig. 4 X-ray crystallographic structures of specific HCV enzymes. (A) NS3-4A proteinase domain (left, bottom): the residues forming the catalytic triad are shown in yellow. A serine-trap inhibitor (compound 2) is covalently linked to the catalytic serine and occupies the enzyme active site. The NS4A cofactor (red) and the bound zinc ion (gray) are shown. (B) NS3 helicase domain: single-stranded nucleic acid bound to the helicase-active site (yellow). Subdomains I, II, and III are recognizable by different colors. (C) NS3-4A proteinase-helicase (middle): the C-terminal product of the NS3/NS4A cleavage reaction occupies the proteinase-active site (gray). (D) NS5B RNA-dependent RNA polymerase (right): the thumb, palm, and finger subdomains are indicated (blue, green, and red, respectively). The two magnesium ions (gray) and the active site aspartates (yellow) are shown in the active site. A GTP molecule is bound at the allosteric site on the surface of the thumb domain. Clinics in Liver Disease 2003 7, 211-242DOI: (10.1016/S1089-3261(02)00069-7)

Fig. 5 Chemical structures of selected inhibitors of the NS3-4A proteinase activity. (A) Serine trap inhibitors, (B) Product-like inhibitors, (C) Non-peptide inhibitors. Clinics in Liver Disease 2003 7, 211-242DOI: (10.1016/S1089-3261(02)00069-7)

Fig. 5 Chemical structures of selected inhibitors of the NS3-4A proteinase activity. (A) Serine trap inhibitors, (B) Product-like inhibitors, (C) Non-peptide inhibitors. Clinics in Liver Disease 2003 7, 211-242DOI: (10.1016/S1089-3261(02)00069-7)

Fig. 6 (A) Chemical structures of selected inhibitors of the NS3 helicase activity. (B) Chemical structures of selected inhibitors of the NS5B RNA-dependent RNA polymerase activity. Clinics in Liver Disease 2003 7, 211-242DOI: (10.1016/S1089-3261(02)00069-7)