title: Discovery of prenylated flavonoids with dual activity against influenza virus and Streptococcus pneumoniae.
abstract: Influenza virus neuraminidase (NA) is the primary target for influenza therapeutics. Severe complications are often related to secondary pneumonia caused by Streptococcus pneumoniae (pneumococci), which also express NAs. Recently, a NA-mediated lethal synergism between influenza A viruses and pneumococci was described. Therefore, dual inhibitors of both viral and bacterial NAs are expected to be advantageous for the treatment of influenza. We investigated the traditional Chinese herbal drug sāng bái pí (mulberry root bark) as source for anti-infectives. Two prenylated flavonoid derivatives, sanggenon G (4) and sanggenol A (5) inhibited influenza A viral and pneumococcal NAs and, in contrast to the approved NA inhibitor oseltamivir, also planktonic growth and biofilm formation of pneumococci. Evaluation of 27 congeners of 5 revealed a correlation between the degree of prenylation and bioactivity. Abyssinone-V 4'-methyl ether (27) inhibited pneumococcal NA with IC50 = 2.18 μM, pneumococcal growth with MIC = 5.63 μM, and biofilm formation with MBIC = 4.21 μM, without harming lung epithelial cells. Compounds 5 and 27 also disrupt the synergism between influenza A virus and pneumococcal NA in vitro, hence functioning as dual-acting anti-infectives. The results warrant further studies on whether the observed disruption of this synergism is transferable to in vivo systems.
authors.affiliation: Department of Pharmacognosy, Faculty of Life Sciences, University of Vienna, Althanstraße 14, 1090 Vienna, Austria.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Grienke
authors.affiliation: Jena University Hospital, Department of Virology and Antiviral Therapy, Hans-Knoell-Strasse 2, 07745 Jena, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Richter
authors.affiliation: Jena University Hospital, Department of Virology and Antiviral Therapy, Hans-Knoell-Strasse 2, 07745 Jena, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Walther
authors.affiliation: Jena University Hospital, Department of Virology and Antiviral Therapy, Hans-Knoell-Strasse 2, 07745 Jena, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Hoffmann
authors.affiliation: University of Hamburg, Center for Bioinformatics, Bundesstrasse 43, 20146 Hamburg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Kirchmair
authors.affiliation: A.N. Bakh Institute of Biochemistry RAS, Leninsky prospekt, 33, build. 2, Moscow, 119071, Russia.
authors.forename: Vadim
authors.initials: V
authors.lastname: Makarov
authors.affiliation: Jena University Hospital, Center of Electron Microscopy, Ziegelmuehlenweg 1, 07743 Jena, Germany.
authors.forename: Sandor
authors.initials: S
authors.lastname: Nietzsche
authors.affiliation: Jena University Hospital, Department of Virology and Antiviral Therapy, Hans-Knoell-Strasse 2, 07745 Jena, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Schmidtke
authors.affiliation: Department of Pharmacognosy, Faculty of Life Sciences, University of Vienna, Althanstraße 14, 1090 Vienna, Austria.
authors.forename: Judith M
authors.initials: JM
authors.lastname: Rollinger
mesh_terms: D001426:Bacterial Proteins / Q000037:antagonists & inhibitors; D001572:Benzofurans / Q000737:chemistry / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects; D002867:Chromones / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D044950:Flavanones / Q000737:chemistry / Q000494:pharmacology*; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology; D009980:Influenza A virus / Q000187:drug effects* / Q000201:enzymology; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D031625:Morus / Q000737:chemistry; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D010933:Plankton / Q000187:drug effects; D018517:Plant Roots / Q000737:chemistry; D054876:Prenylation; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D014764:Viral Proteins / Q000037:antagonists & inhibitors
chemical_list: D001426:Bacterial Proteins; D001572:Benzofurans; D002867:Chromones; D004791:Enzyme Inhibitors; D044950:Flavanones; D005419:Flavonoids; D014764:Viral Proteins; C000608444:sanggenol L; C579694:sanggenon G; D009439:Neuraminidase