Anti−Hepatitis C Virus Drugs in Development Esperance A.K. Schaefer, Raymond T. Chung  Gastroenterology  Volume 142, Issue 6, Pages 1340-1350.e1 (May 2012) DOI: 10.1053/j.gastro.2012.02.015 Copyright © 2012 AGA Institute Terms and Conditions

Figure 1 HCV viral lifecycle, HCV polypeptide structure, and cleavage sites. (A) The HCV viral lifecycle. The virus circulates as a highly lipidated lipoviral particle (LVP). The LVP requires several cells surface receptors for entry (step 1) into the hepatocyte, including scavenger receptor class B1 (SR-B1), CD-81, claudin (CLDN1), and occludin (not pictured). Once internalized, the viral genome is uncoated, revealing the naked viral RNA and viral nucleocapsid. The viral RNA is translated by host ribosomes into the viral polypeptide (step 3), which is then cleaved by a combination of host and viral proteases into the 10 viral proteins. Replication occurs at an endoplasmic reticulum membrane−derived replication complex (the membranous web), which includes the lipid droplet (LD) and nonstructural viral proteins NS4A−NS5B (step 4). Viral replication is also dependent on the participation of key host factors, which include miR-122 and cyclophilin A (CypA). The newly synthesized viral RNA is assembled into new LVP by the Golgi apparatus and subsequently released by the cell (steps 5 and 6). (B) HCV viral genome. The viral genome is a positive-sense, single-stranded RNA genome. The 5′ untranslated region (UTR) contains 2 important domains. The internal ribosome entry site (IRES) directs translation in a cap-independent manner. The 5′ UTR also contains 2 recognition sites by miR-122 that are critical for viral replication. After translation, a single viral polypeptide is generated. The structural proteins are cleaved by host proteases. The NS2/3 autoprotease cleaves the NS2−NS3 junction. The NS3/4A protease initially serves as an autoprotease and separates NS3−NS4A, but then subsequently cleaves the remaining nonstructural proteins. Gastroenterology 2012 142, 1340-1350.e1DOI: (10.1053/j.gastro.2012.02.015) Copyright © 2012 AGA Institute Terms and Conditions

Figure 2 NS5B structure and drug targets. NS5B functions as an RdRp. The structure has a right-handed motif, with structural domains including a finger, thumb, and palm domains and an active, or catalytic site, within a palm subdomain. NIs act at the catalytic site, where they mimic host nucleoside triphosphates (NTPs) and are incorporated into the elongating genome, leading to chain termination. NNIs bind the allosteric sites (palm and thumb), blocking viral replication by way of hindering conformational changes required for activity of the catalytic site. From McGovern BH et al.52 Adapted with permission. Gastroenterology 2012 142, 1340-1350.e1DOI: (10.1053/j.gastro.2012.02.015) Copyright © 2012 AGA Institute Terms and Conditions

Gastroenterology 2012 142, 1340-1350. e1DOI: (10. 1053/j. gastro. 2012 Copyright © 2012 AGA Institute Terms and Conditions

Gastroenterology 2012 142, 1340-1350. e1DOI: (10. 1053/j. gastro. 2012 Copyright © 2012 AGA Institute Terms and Conditions