New 7-methylguanine derivatives targeting the influenza polymerase PB2 cap-binding domain
| Autor: | Oliver Szolar, Antoine Fortuné, Jean-Luc Décout, Andrea Wolkerstorfer, Delphine Guilligay, Thomas Lunardi, Stephen Cusack, Stéphane Pautus, Joe Lewis, Peter Sehr |
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| Rok vydání: | 2013 |
| Předmět: |
Models
Molecular Guanine viruses Crystallography X-Ray Structure-Activity Relationship Viral Proteins Transcription (biology) Heterotrimeric G protein Drug Discovery Structure–activity relationship Polymerase Binding Sites biology Dose-Response Relationship Drug Molecular Structure Chemistry RNA-Dependent RNA Polymerase Molecular biology Biochemistry Viral replication Docking (molecular) Influenza A virus Biotinylation biology.protein Molecular Medicine Binding domain |
| Zdroj: | Journal of medicinal chemistry. 56(21) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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