6NEM

3-hydroxy-5-[(naphthalen-1-yl)methyl]-6-[4-(1H-tetrazol-5-yl)phenyl]pyridin-2(1H)-one bound to influenza 2009 pH1N1 endonuclease

6NEM の概要

• エントリーDOI: 10.2210/pdb6nem/pdb
• 関連するPDBエントリー: 6NEL
• 分子名称: Polymerase acidic protein, MANGANESE (II) ION, 3-hydroxy-5-[(naphthalen-1-yl)methyl]-6-[4-(1H-tetrazol-5-yl)phenyl]pyridin-2(1H)-one, ... (5 entities in total)
• 機能のキーワード: influenza endonuclease inhibitor chelator, viral protein, viral protein-inhibitor complex, viral protein/inhibitor
• 由来する生物種: Influenza A virus (A/Luxembourg/43/2009(H1N1))
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 29161.56

構造登録者

Bauman, J.D.,Arnold, E. (登録日: 2018-12-17, 公開日: 2019-05-01, 最終更新日: 2023-10-11)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.95 Å)