Author:

Keywords:

Science & Technology, Multidisciplinary Sciences, Science & Technology - Other Topics, BIOLOGICAL-ACTIVITIES, DOMAIN, RESISTANT, DISCOVERY, PHARMACOPHORE, VALIDATION, SUBUNIT, Animals, Catalytic Domain, Crystallography, X-Ray, Dogs, Enzyme Inhibitors, HEK293 Cells, Humans, Hydrazones, Hydrogen Bonding, Madin Darby Canine Kidney Cells, Magnesium, Manganese, Metals, Models, Molecular, Molecular Docking Simulation, RNA-Dependent RNA Polymerase, Viral Proteins

Abstract:

Influenza virus PA endonuclease has recently emerged as an attractive target for the development of novel antiviral therapeutics. This is an enzyme with divalent metal ion(s) (Mg(2+) or Mn(2+)) in its catalytic site: chelation of these metal cofactors is an attractive strategy to inhibit enzymatic activity. Here we report the activity of a series of N-acylhydrazones in an enzymatic assay with PA-Nter endonuclease, as well as in cell-based influenza vRNP reconstitution and virus yield assays. Several N-acylhydrazones were found to have promising anti-influenza activity in the low micromolar concentration range and good selectivity. Computational docking studies are carried on to investigate the key features that determine inhibition of the endonuclease enzyme by N-acylhydrazones. Moreover, we here describe the crystal structure of PA-Nter in complex with one of the most active inhibitors, revealing its interactions within the protein's active site.