9C7Y

Structure Of Respiratory Syncytial Virus Polymerase in complex with JNJ-2729

これはPDB形式変換不可エントリーです。

9C7Y の概要

• エントリーDOI: 10.2210/pdb9c7y/pdb
• EMDBエントリー: 45296
• 分子名称: RNA-directed RNA polymerase L, Phosphoprotein, (2S)-1,1,1-trifluoro-2-[5-fluoro-6-(4-fluorophenyl)-4-(2-hydroxypropan-2-yl)pyridin-2-yl]-3-[(4M)-4-(8-methoxyquinolin-6-yl)-1H-1,2,3-triazol-1-yl]propan-2-ol (3 entities in total)
• 機能のキーワード: non-nucleoside inhibitor, complex, polymerase, rsv, viral protein, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Human respiratory syncytial virus A2; 詳細
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 371319.86

構造登録者

Yin, Y.,Tran, M.T.,Yu, X.,Jonckers, T. (登録日: 2024-06-11, 公開日: 2025-01-08)

主引用文献

Tran, M.T.,Grosse, S.,Carbajo, R.J.,Jacoby, E.,Yin, Y.,Yu, X.,Martinez, C.,Stoops, B.,Cooymans, L.,Hu, L.,Lutter, F.H.,Pieters, S.,Tan, E.,Alcazar, J.,Roymans, D.,van Vlijmen, H.,Rigaux, P.,Sharma, S.,Jonckers, T.H.M.
Structure-Activity Relationship of Oxacyclo- and Triazolo-Containing Respiratory Syncytial Virus Polymerase Inhibitors.
Acs Med.Chem.Lett., 15:1549-1558, 2024

PubMed Abstract: Despite the availability of medicines preventing respiratory syncytial virus (RSV) infection, post-exposure treatment options are needed for addressing patient's needs. RSV non-nucleoside polymerase inhibitors (NNI) have emerged as a promising asset for which our group previously disclosed JNJ-8003 with potent antiviral activity and pronounced efficacy. In this work, a structural-guided design to modify the linker vector of JNJ-8003 resulted in the identification of 2-oxacyclo pyridine-containing derivatives whose various ring closing strategies are described. In addition, bioisosteric replacement of an amide bond with triazole retained potency, and cryo-electron microscopy (cryo-EM) confirmed binding in the capping domain. Subsequent NMR conformational analysis suggested a correlation between the potency and conformations. Our efforts have fulfilled the aim of identifying linker modifications with maintained biological activity while enriching structural diversity and allowing modulations of other parameters.

PubMed: 39291020
DOI: 10.1021/acsmedchemlett.4c00272

実験手法

ELECTRON MICROSCOPY (3.24 Å)