Future classes of hepatitis C virus therapeutic agents

Abstract

Recent advances in understanding of the molecular characteristics of the hepatitis C virus have led to the development of novel antiviral therapeutics. Direct-acting antivirals are designed to inhibit viral targets, whereas host-targeted antivirals block host factors that are used by the virus for its own life cycle. The rapid development of agents in multiple classes has led to the promise of shorter therapy duration, an improved side effect profile, and eventually interferon-sparing regimens. This article reviews novel hepatitis C virus therapeutics in development, including mechanism of action, efficacy, and adverse effects.

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). 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 and_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.

Figure 2

Structure of the HCV NS5B RNA-dependent RNA polymerase.

Figure 3. Sequence of miR-122

Below is shown a representation of the two miR-122-binding sites, S1 and S2, located between stem-loop (SL) I and II in the 5′ nontranslated region (5′UTR) of the HCV genome. miR122 interacts with two conserved sites, which contain overlapping cis-acting signals involved in promoting translation of the virus. Adapted from Jangra RK et al. Journal of Virology 2010.