6NEL

4-(2-(4-fluorophenyl)-5-hydroxy-6-oxo-1,6-dihydropyridin-3-yl)benzoic acid bound to influenza 2009 pH1N1 endonuclease

Summary for 6NEL

• Entry DOI: 10.2210/pdb6nel/pdb
• Descriptor: Polymerase acidic protein, MANGANESE (II) ION, MAGNESIUM ION, ... (6 entities in total)
• Functional Keywords: influenza endonuclease inhibitor chelator, viral protein, viral protein-inhibitor complex, viral protein/inhibitor
• Biological source: Influenza A virus (A/Luxembourg/43/2009(H1N1))
• Total number of polymer chains: 1
• Total formula weight: 29060.81

Authors

Bauman, J.D.,Arnold, E. (deposition date: 2018-12-17, release date: 2019-05-01, Last modification date: 2023-10-11)

Primary citation

Sagong, H.Y.,Bauman, J.D.,Nogales, A.,Martinez-Sobrido, L.,Arnold, E.,LaVoie, E.J.
Aryl and Arylalkyl Substituted 3-Hydroxypyridin-2(1H)-ones: Synthesis and Evaluation as Inhibitors of Influenza A Endonuclease.
Chemmedchem, 14:1204-1223, 2019

PubMed Abstract: Seasonal influenza infections are associated with an estimated 250-500 000 deaths annually. Resistance to the antiviral M2 ion-channel inhibitors has largely invalidated their clinical utility. Resistance to neuraminidase inhibitors has also been observed in several influenza A virus (IAV) strains. These data have prompted research on inhibitors that target the cap-snatching endonuclease activity of the polymerase acidic protein (PA). Baloxavir marboxil (Xofluza®), recently approved for clinical use, inhibits cap-snatching endonuclease. Resistance to Xofluza® has been reported in both in vitro systems and in the clinic. An X-ray crystallographic screening campaign of a fragment library targeting IAV endonuclease identified 5-chloro-3-hydroxypyridin-2(1H)-one as a bimetal chelating agent at the active site. We have reported the structure-activity relationships for 3-hydroxypyridin-2(1H)-ones and 3-hydroxyquinolin-2(1H)-ones as endonuclease inhibitors. These studies identified two distinct binding modes associated with inhibition of this enzyme that are influenced by the presence of substituents at the 5- and 6-positions of 3-hydroxypyridin-2(1H)-ones. Herein we report the structure-activity relationships associated with various para-substituted 5-phenyl derivatives of 6-(p-fluorophenyl)-3-hydroxypyridin-2(1H)-ones and the effect of using naphthyl, benzyl, and naphthylmethyl groups as alternatives to the p-fluorophenyl substituent on their activity as endonuclease inhibitors.

PubMed: 30983160
DOI: 10.1002/cmdc.201900084

Experimental method

X-RAY DIFFRACTION (2 Å)