title: New 7-methylguanine derivatives targeting the influenza polymerase PB2 cap-binding domain.
abstract: The heterotrimeric influenza virus polymerase performs replication and transcription of viral RNA in the nucleus of infected cells. Transcription by "cap-snatching" requires that host-cell pre-mRNAs are bound via their 5' cap to the PB2 subunit. Thus, the PB2 cap-binding site is potentially a good target for new antiviral drugs that will directly inhibit viral replication. Docking studies using the structure of the PB2 cap-binding domain suggested that 7-alkylguanine derivatives substituted at position N-9 and N-2 could be good candidates. Four series of 7,9-di- and 2,7,9-trialkyl guanine derivatives were synthesized and evaluated by an AlphaScreen assay in competition with a biotinylated cap analogue. Three synthesized compounds display potent in vitro activity with IC50 values lower than 10 μM. High-resolution X-ray structures of three inhibitors in complex with the H5N1 PB2 cap-binding domain confirmed the binding mode and provide detailed information for further compound optimization.
authors.affiliation: Département de Pharmacochimie Moléculaire, Université de Grenoble Alpes/CNRS, UMR 5063 , ICMG FR 2607, 470 rue de la Chimie, BP 53, F-38041 Grenoble, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Pautus
authors.forename: Peter
authors.initials: P
authors.lastname: Sehr
authors.forename: Joe
authors.initials: J
authors.lastname: Lewis
authors.forename: Antoine
authors.initials: A
authors.lastname: Fortuné
authors.forename: Andrea
authors.initials: A
authors.lastname: Wolkerstorfer
authors.forename: Oliver
authors.initials: O
authors.lastname: Szolar
authors.forename: Delphine
authors.initials: D
authors.lastname: Guilligay
authors.forename: Thomas
authors.initials: T
authors.lastname: Lunardi
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Décout
authors.forename: Stephen
authors.initials: S
authors.lastname: Cusack
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D006147:Guanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D009980:Influenza A virus / Q000201:enzymology*; D008958:Models, Molecular; D015394:Molecular Structure; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C057027:PB2 protein, Influenzavirus A; D014764:Viral Proteins; D006147:Guanine; C008450:7-methylguanine; D012324:RNA-Dependent RNA Polymerase