Targeting the NS5A protein of HCV: An emerging option

Abstract

SUMMARYHepatitis C virus (HCV) infects more than 3% of the world's population, leading to an increased risk of cirrhosis and hepatocellular carcinoma. The current standard of care, a combination of pegylated interferon alfa and ribavirin, is poorly tolerated and often ineffective against the most prevalent genotype of the virus, genotype 1. The very recent approval of boceprevir and telaprevir, two HCV protease inhibitors, promises to significantly improve treatment options and outcomes. In addition to the viral protease NS3 and the viral polymerase NS5B, direct-acting antivirals are now in development against NS5A. A multifunctional phosphoprotein, NS5A is essential to HCV genome replication, but has no known enzymatic function. Here we report how the design of small-molecule inhibitors against NS5A has evolved from promising monomers to highly potent dimeric compounds effective against many HCV genotypes. We also highlight recent clinical data and how the inhibitors may bind to NS5A, itself capable of forming dimers. HEPATITIS C VIRUS (HCV): AN INTERNATIONAL HEALTH CONCERNHepatitis C virus (HCV) infects approximately 170 million individuals, with an estimated 2.3-4.7 million new infections each year (1). The primary mode of transmission of HCV is via exposure to infected blood, including transfusions from infected donors, and through injection drug use. It is estimated that 15-30% of all HCV infections will spontaneously clear, but the remaining 70-85% of infections will develop into chronic hepatitis (2, 3). Chronic infections can subsequently lead to steatosis, cirrhosis and hepatocellular carcinoma (4). Among all recognized positive-strand RNA viruses, the ability to establish a chronic infection is exclusive to HCV (5), although how the virus mediates persistence remains unknown.Current treatment options for HCV are relatively poor. The standard of care is often a grueling 48-week combination of pegylated interferon alfa (IFN-α) and the nucleoside analogue ribavirin. Effective clearance of the virus is achieved in less than 50% of genotype

Expanding the Proteome of an RNA Virus by Phosphorylation of an Intrinsically Disordered Viral Protein

“…HCV NS5A contributes to genome replication, virion assembly, and myriad interactions with the host cell (7). How this protein interfaces with so many different viral and cellular pathways is unknown.…”

“…One of these dimers binds to RNA, with a preference for GU-rich RNA (3,4). The carboxyl-terminal domain is an intrinsically disordered domain (IDD) (5,6) that contains numerous putative sites of phosphorylation and has been reported to bind dozens of cellular proteins (7). The ability of NS5A to antagonize and/or to hijack numerous cellular pathways may be a key determinant of HCV persistence.…”

Intragenic Complementation of Hepatitis C Virus NS5A RNA Replication-Defective Alleles

“…While the biological relevance of many of these interactions remains unclear, others play important roles in HCV replication (3). NS5A consists of an N-terminal amphipathic alpha helix (amino acids 5 to 25) that targets NS5A to intracellular membranes and three structural domains (I, II, and III) separated by regions of low-complexity sequence (LCS I and LCS II) (4)(5)(6)(7).…”

The lysine methyltransferase SMYD3 interacts with hepatitis C virus NS5A and is a negative regulator of viral particle production

“…NS5A is a multifunctional, RNA-binding phosphoprotein with key functions in HCV replication and assembly. In addition, NS5A manipulates various cellular pathways to generate an intracellular environment favoring viral replication (Cordek et al, 2011). …”

“…Thus far, no enzymatic activity has been ascribed to NS5A and although it has been subject to intensive research, the molecular events required for the various effects of NS5A are far from being fully understood. Nevertheless, differential interactions with host as well as viral proteins seem to form the basis of NS5A function (Cordek et al, 2011). …”