title: Discovery and Characterization of Diazenylaryl Sulfonic Acids as Inhibitors of Viral and Bacterial Neuraminidases.
abstract: Viral neuraminidases are an established drug target to combat influenza. Severe complications observed in influenza patients are primarily caused by secondary infections with e.g.,Streptococcus pneumoniae. These bacteria engage in a lethal synergism with influenza A viruses (IAVs) and also express neuraminidases. Therefore, inhibitors with dual activity on viral and bacterial neuraminidases are expected to be advantageous for the treatment of influenza infections. Here we report on the discovery and characterization of diazenylaryl sulfonic acids as dual inhibitors of viral andStreptococcus pneumoniaeneuraminidase. The initial hit came from a virtual screening campaign for inhibitors of viral neuraminidases. For the most active compound, 7-[2-[4-[2-[4-[2-(2-hydroxy-3,6-disulfo-1-naphthalenyl)diazenyl]-2-methylphenyl]diazenyl]-2-methylphenyl]diazenyl]-1,3-naphthalenedisulfonic acid (NSC65847;1), theKi-values measured in a fluorescence-based assay were lower than 1.5 μM for both viral and pneumococcal neuraminidases. The compound also inhibited N1 virus variants containing neuraminidase inhibitor resistance-conferring substitutions. Via enzyme kinetics and nonlinear regression modeling,1was suggested to impair the viral neuraminidases and pneumococcal neuraminidase with a mixed-type inhibition mode. Given its antiviral and antipneumococcal activity,1was identified as a starting point for the development of novel, dual-acting anti-infectives.
authors.affiliation: Department of Virology and Antiviral Therapy, Jena University Hospital Jena, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Hoffmann
authors.affiliation: Department of Virology and Antiviral Therapy, Jena University Hospital Jena, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Richter
authors.affiliation: Centre for Chemistry and Biomedicine, Institute of General, Inorganic and Theoretical Chemistry, University of Innsbruck Innsbruck, Austria.
authors.forename: Susanne
authors.initials: S
authors.lastname: von Grafenstein
authors.affiliation: Department of Virology and Antiviral Therapy, Jena University Hospital Jena, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Walther
authors.affiliation: Department of Virology and Antiviral Therapy, Jena University Hospital Jena, Germany.
authors.forename: Zhongli
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Virology and Antiviral Therapy, Jena University Hospital Jena, Germany.
authors.forename: Lilia
authors.initials: L
authors.lastname: Schumann
authors.affiliation: Department of Pharmacognosy, Faculty of Life Sciences, University of Vienna Vienna, Austria.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Grienke
authors.affiliation: Department of Pharmacognosy, Faculty of Life Sciences, University of Vienna Vienna, Austria.
authors.forename: Christina E
authors.initials: CE
authors.lastname: Mair
authors.affiliation: Centre for Chemistry and Biomedicine, Institute of General, Inorganic and Theoretical Chemistry, University of Innsbruck Innsbruck, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Kramer
authors.affiliation: Department of Pharmacognosy, Faculty of Life Sciences, University of Vienna Vienna, Austria.
authors.forename: Judith M
authors.initials: JM
authors.lastname: Rollinger
authors.affiliation: Centre for Chemistry and Biomedicine, Institute of General, Inorganic and Theoretical Chemistry, University of Innsbruck Innsbruck, Austria.
authors.forename: Klaus R
authors.initials: KR
authors.lastname: Liedl
authors.affiliation: Department of Virology and Antiviral Therapy, Jena University Hospital Jena, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Schmidtke
authors.affiliation: Centre for Chemistry and Biomedicine, Institute of General, Inorganic and Theoretical Chemistry, University of InnsbruckInnsbruck, Austria; Center for Bioinformatics, University of HamburgHamburg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Kirchmair
keywords: Streptococcus pneumoniae; coinfection; diazenylaryl sulfonic acid; influenza virus; neuraminidase; small molecule inhibitor