Crystal structure of the N-terminal zinc-binding domain of HCV NS5A (PDB ID=1ZH1), the proposed target of BMS-790052 (inset) Hepatitis C virus (HCV) is a leading cause of liver disease and the current ‘standard of care’ treatment, a combination of pegylated interferon-α and ribavirin, is expensive, can cause serious side effects and is only effective for some patients. There are at least 6 known HCV genotypes, with several subtypes and quasispecies within each genotype and these all respond differently to treatment – the combination of pegylated interferon-α and ribavirin is able to clear the virus from about half of patients infected with genotype 1 HCV. In the search for more effective treatments, a number of groups are developing compounds that specifically target HCV. Inhibitors of the viral NS3 serine protease and the NS5B4 RNA-dependent RNA polymerase have already entered the clinic and researchers at Bristol-Myers Squibb have now reported that a compound with a new mechanism of action, BMS-790052, led to dramatic reductions in viral load and produced few side effects in a phase I clinical study. BMS-790052 targets NS5A, an HCV non-structural protein that possesses no enzymatic activity and is thought to regulate viral replication and host cell interactions. The compound, which was identified using a chemical genetics strategy, is active at picomolar concentrations in vitro towards replicons expressing a broad range of HCV genotypes and acts additively to synergistically with interferon and other small molecule antiviral compounds.
The study, which is published in the journal Nature, provides the first clinical evidence that targeting NS5A may be an effective strategy for treating patients who are chronically infected with HCV. Future treatments for HCV infection may involve ‘cocktails’ of drugs that target specific stages in the viral lifecycle, just as HIV infection is managed now, although whether it will be possible to drop interferon from HCV treatment combinations remains to be seen.
