October 18 | 2013

New 7-methyl-guanosine derivatives targeting the influenza polymerase PB2 cap-binding domain

Authors | Pautus S, Sehr P, Lewis J, Fortune A, Wolkerstorfer A, Szolar O, Guilligay D, Lunardi T, Decout JL, Cusack S

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-tri-alkyl guanine derivatives were synthesized and evaluated by an AlphaScreen assay in competition with a biotinylated cap analogue. Three synthesised compounds display potent in vitro activity with IC50 lower than 10 mM. 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.

J. Med. Chem. 18 Oct 2013 [Epub ahead of print] PMID: 24134208

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