Daclatasvir inhibits hepatitis C virus NS5A motility and hyper-accumulation of phosphoinositides.

摘要: Abstract Combinations of direct-acting antivirals (DAAs) against the hepatitis C virus (HCV) have potential to revolutionize HCV therapeutic regime. An integral component DAA combination therapies is NS5A inhibitors. It has previously been proposed that DAAs inhibit two functions NS5A: RNA replication and virion assembly. In this study, we characterize impact a prototype DAA, daclatasvir (DCV), on compartment formation. DCV impaired replicase localization motility. order mechanism behind altered localization, examined interaction with its essential cellular cofactor, phosphatidylinositol-4-kinase III α (PI4KA). We observed does not PI4KA directly, nor it impair early events NS5A–PI4KA can occur when expressed alone. are unaffected by include binding, as determined co-immunoprecipitation, basal accumulation product, PI4P. However, impairs late steps in activation requires context polyprotein. These hyper-stimulation PI4P levels appropriate The data most consistent model wherein inhibits conformational changes protein or complex formations polyprotein expression stimulate hyper-accumulation