Article

Projet
 
Antoine FORTUNE, Jean-Luc DECOUT,   
Titre
New 7-methylguanine derivatives targeting the influenza PB2 cap-binding domain.  
[Full paper ]
Auteurs
S. Pautus, P. Sehr, J. Lewis, A. Fortuné, A. Wolkerstorfer, O. Szolar, D. Guilligay, T. Lunardi, J.-L. Decout, S. Cusack.
Edition
J. Med. Chem. 2013, 56, 8915-8930.
Année
2013
Résumé
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 derivs. substituted at position N-​9 and N-​2 could be good candidates. Four series of 7,​9-​di- and 2,​7,​9-​trialkyl guanine derivs. were synthesized and evaluated by an AlphaScreen assay in competition with a biotinylated cap analog. Three synthesized compds. (e.g., I) display potent in vitro activity with IC50 values lower than 10 μM. High-​resoln. 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 compd. optimization.