title: The fight against the influenza A virus H1N1: synthesis, molecular modeling, and biological evaluation of benzofurazan derivatives as viral RNA polymerase inhibitors.
abstract: The influenza RNA polymerase complex, which consists of the three subunits PA, PB1, and PB2, is a promising target for the development of new antiviral drugs. A large library of benzofurazan compounds was synthesized and assayed against influenza virus A/WSN/33 (H1N1). Most of the new derivatives were found to act by inhibiting the viral RNA polymerase complex through disruption of the complex formed between subunits PA and PB1. Docking studies were also performed to elucidate the binding mode of benzofurazans within the PB1 binding site in PA and to identify amino acids involved in their mechanism of action. The predicted binding pose is fully consistent with the biological data and lays the foundation for the rational development of more effective PA-PB1 inhibitors.
authors.affiliation: Dipartimento Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. De Gasperi 2, 53100 Siena (Italy).
authors.forename: Mafalda
authors.initials: M
authors.lastname: Pagano
authors.forename: Daniele
authors.initials: D
authors.lastname: Castagnolo
authors.forename: Martina
authors.initials: M
authors.lastname: Bernardini
authors.forename: Anna Lucia
authors.initials: AL
authors.lastname: Fallacara
authors.forename: Ilaria
authors.initials: I
authors.lastname: Laurenzana
authors.forename: Davide
authors.initials: D
authors.lastname: Deodato
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kessler
authors.forename: Beatrice
authors.initials: B
authors.lastname: Pilger
authors.forename: Lilli
authors.initials: L
authors.lastname: Stergiou
authors.forename: Stephan
authors.initials: S
authors.lastname: Strunze
authors.forename: Cristina
authors.initials: C
authors.lastname: Tintori
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001583:Benzoxazoles / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000201:enzymology*; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D060066:Protein Interaction Maps / Q000187:drug effects; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000378:metabolism; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D001583:Benzoxazoles; D004791:Enzyme Inhibitors; D021122:Protein Subunits; D014764:Viral Proteins; C020160:benzofurazan; D012321:DNA-Directed RNA Polymerases
keywords: H1N1; RNA polymerase; antiviral agents; benzofurazans; influenza A