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With the introduction of direct-acting antivirals (DAA), the treatment for chronic hepatitis C is evolving at an astonishingly rapid pace.1 Among DAAs, HCV NS5A inhibitors show substantial promise as anti-HCV therapeutics. NS5A inhibitors in clinical development include daclatasvir (DCV), ledipasvir, ombitasvir and MK-8742.2 With in vitro anti-HCV activities in the low picomolar range, these represent the most potent class of DAAs to target HCV. The HCV NS5A protein is known to function in multiple aspects of the HCV life cycle, including roles in viral replication and assembly, as well as complex interactions with cellular factors. Not being associated with any measurable enzymatic activity, NS5A was not considered ‘druggable’ for a very long time. In fact, the first small-molecule NS5A inhibitors were discovered by random screening using the HCV replicon system. The initial lead compounds had only moderate potency, but subsequent medicinal chemistry efforts resulted in the discovery of drugs with unparalleled antiviral activity that are characterised by highly symmetrical dimeric structure.3 The most studied of these ‘palindromic’ NS5A inhibitor class is DCV4 (formerly BMS-790052), a DAA active against a broad range of HCV genotypes for which regulatory approval both in interferon (IFN)-containing or IFN-free regimens is currently being sought. Sequencing of replicons resistant to DCV and related compounds identified NS5A as their molecular target.5 ,6 In particular, variants of NS5A M28, Q30, L31 and Y93 were found to be the most common mutations conferring broad resistance to this class of antivirals. Y93, the …
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