6S5V

Crystal structure of the Cap-Midlink region of the H5N1 Influenza A virus polymerase in complex with a Cap-domain binding analogue

This is a non-PDB format compatible entry.

Summary for 6S5V

• Entry DOI: 10.2210/pdb6s5v/pdb
• Descriptor: Polymerase basic protein 2, (1~{S},2~{S},3~{S},6~{R})-2-[[2-[5,7-bis(fluoranyl)-1~{H}-indol-3-yl]-5-fluoranyl-pyrimidin-4-yl]amino]-3,6-dimethyl-cyclohexane-1-carboxylic acid, GLYCEROL, ... (5 entities in total)
• Functional Keywords: influenza a, h5n1, influenza polymerase, cap binding analogue, viral protein
• Biological source: Influenza A virus (A/duck/Fujian/13/2002(H5N1))
• Total number of polymer chains: 2
• Total formula weight: 70068.95

Authors

Keown, J.R.,Fodor, E.,Grimes, J.M. (deposition date: 2019-07-02, release date: 2019-11-06, Last modification date: 2024-05-15)

Primary citation

McGowan, D.C.,Balemans, W.,Embrechts, W.,Motte, M.,Keown, J.R.,Buyck, C.,Corbera, J.,Funes, M.,Moreno, L.,Cooymans, L.,Tahri, A.,Eymard, J.,Stoops, B.,Strijbos, R.,Van den Berg, J.,Fodor, E.,Grimes, J.M.,Koul, A.,Jonckers, T.H.M.,Raboisson, P.,Guillemont, J.
Design, Synthesis, and Biological Evaluation of Novel Indoles Targeting the Influenza PB2 Cap Binding Region.
J.Med.Chem., 62:9680-9690, 2019

PubMed Abstract: In the search for novel influenza inhibitors we evaluated 7-fluoro-substituted indoles as bioisosteric replacements for the 7-azaindole scaffold of Pimodivir, a PB2 (polymerase basic protein 2) inhibitor currently in clinical development. Specifically, a 5,7-difluoroindole derivative was identified as a potent and metabolically stable influenza inhibitor. demonstrated a favorable oral pharmacokinetic profile and in vivo efficacy in mice. In addition, it was found that was not at risk of metabolism via aldehyde oxidase, an advantage over previously described inhibitors of this class. The crystal structure of bound to influenza A PB2 cap region is disclosed here and deposited to the PDB.

PubMed: 31647875
DOI: 10.1021/acs.jmedchem.9b01091

Experimental method

X-RAY DIFFRACTION (1.35 Å)