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The Fight against the Influenza A Virus H1N1: Synthesis, Molecular Modeling, and Biological Evaluation of Benzofurazan Derivatives as Viral RNA Polymerase Inhibitors
Author(s) -
Pagano Mafalda,
Castagnolo Daniele,
Bernardini Martina,
Fallacara Anna Lucia,
Laurenzana Ilaria,
Deodato Davide,
Kessler Ulrich,
Pilger Beatrice,
Stergiou Lilli,
Strunze Stephan,
Tintori Cristina,
Botta Maurizio
Publication year - 2014
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201300378
Subject(s) - polymerase , rna polymerase , influenza a virus , virus , virology , docking (animal) , rna , chemistry , binding site , biology , biochemistry , enzyme , gene , medicine , nursing
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.