title: Biflavonoids of Dacrydium balansae with potent inhibitory activity on dengue 2 NS5 polymerase.
abstract: In order to find new molecules for antiviral drug design, we screened 102 ethyl acetate extracts from New-Caledonian flora for antiviral activity against the dengue 2 virus RNA-dependant RNA polymerase (DV-NS5 RdRp). The leaf extract of Dacrydium balansae, which strongly inhibited the DV-NS5, was submitted to bioguided fractionation. Four biflavonoids ( 1- 4), three sterols ( 5- 7), and two stilbene derivatives ( 8- 9) were identified and evaluated for their antiviral potential on the DV-NS5 RdRp. Biflavonoids appeared to be potent inhibitors of DV-NS5 RdRp with IC (50)s between 0.26 and 3.12 µM. Inhibitory activity evaluations against the RNA polymerase from other Flaviviridae viruses allowed us to conclude that these compounds are specific inhibitors of the DV RNA polymerase. The strongest inhibitions were observed with hinokiflavone ( 4), but podocarpusflavone A ( 2) is the strongest noncytotoxic inhibitor of the DV-NS5 and it also displayed polymerase inhibitory activity in a DV replicon. A preliminary structure-activity relationship study (SARs) revealed the necessity of the biflavonoid skeleton, the influence of number and position of methoxylations, and the importance of a free rotation of the linkage between the two apigenin monomers of the biflavonoids. To the best of our knowledge, podocarpusflavone A ( 2) is the strongest noncytotoxic non-nucleotide molecule exhibiting a specific inhibitory activity against the RNA polymerase domain of DV-NS5 and thus is promising for chemotherapy development against dengue fever.
authors.affiliation: Laboratoire Insulaire du Vivant et de l'Environnement, Université de la Nouvelle-Caledonie, Nouméa Cedex, Nouvelle-Calédonie, France.
authors.forename: Paul
authors.initials: P
authors.lastname: Coulerie
authors.forename: Cécilia
authors.initials: C
authors.lastname: Eydoux
authors.forename: Edouard
authors.initials: E
authors.lastname: Hnawia
authors.forename: Laetitia
authors.initials: L
authors.lastname: Stuhl
authors.forename: Alexandre
authors.initials: A
authors.lastname: Maciuk
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lebouvier
authors.forename: Bruno
authors.initials: B
authors.lastname: Canard
authors.forename: Bruno
authors.initials: B
authors.lastname: Figadère
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Guillemot
authors.forename: Mohammed
authors.initials: M
authors.lastname: Nour
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D044946:Biflavonoids / Q000737:chemistry / Q000494:pharmacology*; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D003716:Dengue Virus / Q000187:drug effects / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D009510:New Caledonia; D008517:Phytotherapy; D024301:Plant Bark / Q000737:chemistry; D018515:Plant Leaves / Q000737:chemistry; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D064028:Tracheophyta / Q000737:chemistry*; D017361:Viral Nonstructural Proteins / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D044946:Biflavonoids; D004791:Enzyme Inhibitors; D017361:Viral Nonstructural Proteins; D012324:RNA-Dependent RNA Polymerase; D012321:DNA-Directed RNA Polymerases