4CB4

Structure of Influenza A H5N1 PB2 cap-binding domain with bound m7GTP

Summary for 4CB4

• Entry DOI: 10.2210/pdb4cb4/pdb
• Related: 4CB5
• Descriptor: POLYMERASE BASIC SUBUNIT 2, 7N-METHYL-8-HYDROGUANOSINE-5'-TRIPHOSPHATE, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: transferase, cap-binding inhibitors
• Biological source: INFLUENZA A VIRUS
• Total number of polymer chains: 1
• Total formula weight: 19533.53

Authors

Pautus, S.,Sehr, P.,Lewis, J.,Fortune, A.,Wolkerstorfer, A.,Szolar, O.,Gulligay, D.,Lunardi, T.,Decout, J.L.,Cusack, S. (deposition date: 2013-10-10, release date: 2013-10-30, Last modification date: 2023-12-20)

Primary citation

Pautus, S.,Sehr, P.,Lewis, J.,Fortune, A.,Wolkerstorfer, A.,Szolar, O.,Gulligay, D.,Lunardi, T.,Decout, J.L.,Cusack, S.
New 7-Methyl-Guanosine Derivatives Targeting the Influenza Polymerase Pb2 CAP-Binding Domain
J.Med.Chem., 56:8915-, 2013

PubMed 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.

PubMed: 24134208
DOI: 10.1021/JM401369Y

Experimental method

X-RAY DIFFRACTION (1.6 Å)