Journal of Medicinal Chemistry p. 8915 - 8930 (2013)
Update date:2022-08-15
Topics:
Pautus, Stéphane
Sehr, Peter
Lewis, Joe
Fortuné, Antoine
Wolkerstorfer, Andrea
Szolar, Oliver
Guilligay, Delphine
Lunardi, Thomas
Décout, Jean-Luc
Cusack, Stephen
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.
View MoreContact:+1-973-357-0577
Address:10 Taft Rd.
Taixing Shenfeng Chemical Co., Ltd.
Contact:+86-523-87117033, 87117666
Address:4# Yinsanlu, Huangqiao town, Taixing, Jiangsu, China.
Anhui Qingyun Pharmaceutical and Chemical Co.,Ltd
Contact:+86-551-63633067
Address:Shuangfeng Road Hefei Anhui
Chiral Quest (Suzhou) Company Ltd
website:http://www.chiralquest.com
Contact:+86-0512-62956066
Address:B1/9, 218 Xinghu Street, Suzhou Industrial Park
Jiangsu Willing Bio-Tech Co ltd
website:http://www.willingbio.com/
Contact:+86 18796909136
Address:No 18 Guoqiao Road
Doi:10.1007/BF00955813
(1987)Doi:10.1016/S0040-4020(01)97425-3
(1974)Doi:10.1021/ol800284g
(2008)Doi:10.3762/bjoc.8.219
(2012)Doi:10.1016/S0040-4020(00)01148-0
(2001)Doi:10.1055/s-2001-9719
(2001)