Targeting HCV Entry For Development of Therapeutics

Jeffrey F Mckelvy,Andrew J Syder,Flossie Wong-Staal

doi:10.3390/v2081718

Abstract

Recent progress in defining the molecular mechanisms of Hepatitis C Virus (HCV) entry affords the opportunity to exploit new viral and host targets for therapeutic intervention. Entry inhibitors would limit the expansion of the infected cell reservoir, and would complement the many replication inhibitors now under development. The current model for the pathway of entry involves the initial docking of the virus onto the cell surface through interactions of virion envelope and associated low density lipoproteins (LDL) with cell surface glycosaminoglycans and lipoprotein receptors, followed by more specific utilization with other hepatocyte membrane proteins: Scavenger Receptor Class B type 1 (SR-BI), CD81, Claudin 1 (CLDN1) and Occludin (OCLN). The use of blockers of these interactions, e.g. specific antibodies, suggests that inhibition of any one step in the entry pathway can inhibit infection. Despite this knowledge base, the tools for compound screening, HCV pseudoparticles (HCVpp) and cell culture virus (HCVcc), and the ability to adapt them to industrial use are only recently available and as a result drug discovery initiatives are in their infancy. Several therapies aiming at modulating the virus envelope to prevent host cell binding are in early clinical testing. The first test case for blocking a cellular co-receptor is an SR-BI modulator. ITX 5061, an orally active small molecule, targets SR-BI and has shown potent antiviral activity against HCVpp and HCVcc. ITX 5061 has exhibited good safety in previous clinical studies, and is being evaluated in the clinic in chronic HCV patients and patients undergoing liver transplantation. Entry inhibitors promise to be valuable players in the future development of curative therapy against HCV.

Highlights

Hepatitis C virus (HCV) infection is a global disease of high prevalence
The ability to more effectively treat HCV has awaited scientific advances which enable targeted drug discovery. These have come in the form of the replicon system, facilitating the screening of compounds that inhibit viral replication [2], and the pseudotyped virus assay (HCVpp) [3,4], which allows screening of drugs that inhibit entry of viruses bearing the HCV envelope proteins
The first generation of direct acting HCV anti-virals is being developed as triple therapy with standard of care (SOC), namely interferon–ribavirin (INT/RBV), because single agent studies have shown the rapid emergence of resistant mutants

Summary

Introduction

Hepatitis C virus (HCV) infection is a global disease of high prevalence. Remarkably, there is a single treatment option – a combination of subcutaneous -interferon and oral ribavirin – which, at least in part due to intolerability and contraindication issues, provides effective treatment to only a minority of patients at the community level (as opposed to the clinical trial population) [1]. The first generation of direct acting HCV anti-virals is being developed as triple therapy with standard of care (SOC), namely interferon–ribavirin (INT/RBV), because single agent studies have shown the rapid emergence of resistant mutants. This experience is very similar to that of HIV therapies, suggesting that successful treatment of HCV will require combination therapies with different mechanisms. In the quest for direct acting anti-virals, most companies have targeted viral genes involved in replication: protease and polymerase inhibitors and other non–structural proteins (e.g., NS5A) [13], while relatively little effort has been directed at host targets This is a logical approach with evident. Greater detail will be presented on our own compound, ITX5061, a small molecule antagonist of SR-BI, a cellular co-receptor of HCV

The HCV Entry Process

Targeting the Viral Envelope Proteins

Random Screening for HCV Entry Inhibitors

Findings

Perspective