Host-targeting agents in the treatment of hepatitis C: A beginning and an end?

Abstract

The development of two distinct classes of hepatitis C antiviral agents, direct-acting antivirals (DAAs) and host-targeting antivirals (HTAs), have distinctly impacted the hepatitis C virus (HCV) field by generating higher sustained virological response (SVR) rates within infected patients, via reductions in both adverse side effects and duration of treatment when compared to the old standard of care. Today DAAs are actively incorporated into the standard of care and continue to receive the most advanced clinical trial analysis. With a multitude of innovative and potent second-generation DAA compounds currently being tested in clinical trials, it is clear that the future of DAAs looks very bright. In comparison to the other class of compounds, HTAs have been slightly less impactful, despite the fact that primary treatment regimens for HCV began with the use of an HTA - interferon alpha (IFNα). The compound was advantageous in that it provided a broad-reaching antiviral response; however deleterious side effects and viral/patient resistance has since made the compound outdated. HTA research has since moved onward to target a number of cellular host factors that are required for HCV viral entry and replication such as scavenger receptor-BI (SR-BI), 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCoA reductase), cyclophilin A (CypA), fatty acid synthase (FASN) and miRNA-122. The rationale behind pursuing these HTAs is based upon the extremely low mutational rate that occurs within eukaryotic cells, thereby creating a high genetic barrier to drug resistance for anti-HCV compounds, as well as pan-genotypic coverage to all HCV genotypes and serotypes. As the end appears near for HCV, it becomes important to ask if the development of novel HTAs should also be analyzed in combination with other DAAs, in order to address potential hard-to-treat HCV patient populations. Since the treatment regimens for HCV began with the use of a global HTA, could one end the field as well?

Seed Sequence-Matched Controls Reveal Limitations of Small Interfering RNA Knockdown in Functional and Structural Studies of Hepatitis C Virus NS5A-MOBKL1B Interaction

“…We showed that the MOBKL1B binding site on NS5A overlapped with the binding site of cyclophilin A (CypA), a cellular protein that is essential for HCV RNA replication, as its interaction with NS5A enhances HCV RNA binding (11)(12)(13)(14). CypA has emerged as the first host factor targeted for anti-HCV therapy, and drugs blocking the CypA-NS5A interaction are currently in various stages of clinical development (15). Mutant HCVs that replicate in the absence of CypA have amino acid substitutions in the CypA binding site of NS5A, and because of the overlap of the MOBKL1B and CypA binding sites, we questioned whether these mutations would also affect NS5A-MOBKL1B interactions.…”

Interferon-Free Strategies without a Nucleoside/Nucleotide Analogue

“…HTAs inhibit for example viral entry factors, kinases, micro-RNAs, or enzymes involved in viral replication (reviewed in 63,64 ). Monoclonal antibodies directed against viral entry factors (e.g., CD81-mAbs, anti-SR-BI mAbs, ITX5061), or EGFR kinase (erlotinib) and the cholesterol absorption NPC1L1 inhibitor ezetimibe have been shown to protect or delay HCV infection in mice.…”

Identification of a novel epitope in the C terminus of hepatitis C virus-E2 protein that induces potent and cross-reactive neutralizing antibodies

“…Hepatitis C virus (HCV) infection is a major health problem worldwide, affecting more than 170 million people, and causing viral hepatitis, which often leads to hepatocellular carcinoma [1,2]. In India, HCV genotype 3a is prevalent followed by genotype 1b [3].…”