HCV drug discovery aimed at viral eradication

Abstract

Hepatitis C virus (HCV) causes significant morbidity and mortality worldwide with nearly 3% of the world population infected by this virus. Fortunately, this virus does not establish latency, and hence it may be possible to eradicate it. HCV is strongly associated with liver cirrhosis and hepatocellular carcinoma and is currently treated with pegylated interferon-alpha (peg-IFN-alpha) and ribavirin. Unfortunately, these limited treatment options often produce significant side effects, and currently, complete eradication of virus with combined drug modalities has not yet been achieved for the majority of chronically HCV-infected individuals. Restricted treatment options, lack of a universal cure for HCV and the link between chronic infection, liver cirrhosis and hepatocellular carcinoma necessitate design of novel drugs and treatment options. Understanding the relationship between the immune response, viral clearance and inhibition of viral replication with pharmacology-based design can ultimately allow for complete eradication of HCV. This review focuses upon significant novel preclinical and clinical specifically targeted antiviral therapy (STAT-C) drugs under development, highlights their mechanism of action, and discusses their impact on systemic viral loads and permanent clearance of infection.

Fig. 1

Anti-HCV therapies under clinical investigation arranged by phase of clinical investigation.

Fig. 2

(a) Mechanism of action for HCV entry inhibitors. Potential sites for targeted inhibition include receptors implicated in HCV entry including CD81, Claudin 1 [CLDN1], Glycosaminoglycan [GAG], Scavenger receptor type B1 [SRB1], and Low density lipoprotein receptor [LDLR]. (b) Mechanism of immunomodulators for treatment of HCV infection. Toll-like receptor [TLR] mediated production of proinflammatory cytokines TNF-α, IL-12 and IFN-α results in enhanced adaptive and innate immunity hallmarked by increased antibody production, cytotoxic function and increase phagocytic activity (1, 2, 11–12, 1522, 77, 79, 107).