title: N-acylhydrazone inhibitors of influenza virus PA endonuclease with versatile metal binding modes.
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.
authors: Dipartimento di Chimica and Consorzio Interuniversitario di Ricerca in Chimica dei Metalli nei Sistemi Biologici, Università di Parma, Parco Area delle Scienze 17/A, 43124 Parma, Italy.
authors: Mauro
authors: M
authors: Carcelli
authors: Dipartimento di Chimica and Consorzio Interuniversitario di Ricerca in Chimica dei Metalli nei Sistemi Biologici, Università di Parma, Parco Area delle Scienze 17/A, 43124 Parma, Italy.
authors: Dominga
authors: D
authors: Rogolino
authors: Dipartimento di Chimica and Consorzio Interuniversitario di Ricerca in Chimica dei Metalli nei Sistemi Biologici, Università di Parma, Parco Area delle Scienze 17/A, 43124 Parma, Italy.
authors: Anna
authors: A
authors: Gatti
authors: Dipartimento di Scienze del Farmaco e Prodotti per la Salute, Università di Messina, Polo Universitario SS. Annunziata, 98158 Messina, Italy.
authors: Laura
authors: L
authors: De Luca
authors: Dipartimento di Chimica e Farmacia, Università di Sassari, Via Vienna 2, I-07100 Sassari, Italy.
authors: Mario
authors: M
authors: Sechi
authors: Dept. of Structural Biology, St. Jude Children's Research Hospital, 262, Danny Thomas Place, Mail Stop 311, Memphis, TN 38105 USA.
authors: Gyanendra
authors: G
authors: Kumar
authors: Dept. of Structural Biology, St. Jude Children's Research Hospital, 262, Danny Thomas Place, Mail Stop 311, Memphis, TN 38105 USA.
authors: Stephen W
authors: SW
authors: White
authors: Rega Institute for Medical Research, KU Leuven - University of Leuven, B-3000 Leuven, Belgium.
authors: Annelies
authors: A
authors: Stevaert
authors: Rega Institute for Medical Research, KU Leuven - University of Leuven, B-3000 Leuven, Belgium.
authors: Lieve
authors: L
authors: Naesens
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004285:Dogs; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D006835:Hydrazones / Q000737:chemistry / Q000494:pharmacology*; D006860:Hydrogen Bonding; D061985:Madin Darby Canine Kidney Cells; D008274:Magnesium / Q000737:chemistry; D008345:Manganese / Q000737:chemistry; D008670:Metals / Q000737:chemistry*; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D006835:Hydrazones; D008670:Metals; C061290:PA protein, influenza viruses; D014764:Viral Proteins; D008345:Manganese; D012324:RNA-Dependent RNA Polymerase; D008274:Magnesium