9ED2

CryoEM map of Respiratory Syncytial Virus Polymerase with Non-Nucleoside Inhibitor compound 21

これはPDB形式変換不可エントリーです。

9ED2 の概要

• エントリーDOI: 10.2210/pdb9ed2/pdb
• EMDBエントリー: 47931
• 分子名称: RNA-directed RNA polymerase L, Phosphoprotein, Compound 21, ... (4 entities in total)
• 機能のキーワード: non-nucleoside inhibitor, complex, polymerase, rsv, viral protein, viral protein-inhibitor complex, viral protein/inhibitor
• 由来する生物種: human respiratory syncytial virus; 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 371114.16

構造登録者

Yin, Y.,Tran, M.T.,Yu, X.,Jonckers, T.,Carney, S. (登録日: 2024-11-15, 公開日: 2025-09-24)

主引用文献

Carney, S.M.,Grosse, S.,Yin, Y.,Tran, M.T.,Kalin, J.H.,Jacoby, E.,Fung, A.,Simmons, N.,Xie, X.,Bhaumik, A.,Carbajo, R.J.,Piassek, M.,Miller, R.,Hu, L.,Lemmens, C.,Lutter, F.H.,Pieters, S.,Rombouts, G.,Vetrano, I.,Oehlrich, D.,Tomaso, S.,Lozada, K.,Garcia, M.O.,Anson, B.,De Bruyn, S.,Smith-Monroy, C.,Neefs, J.M.,Conceicao-Neto, N.,Kesteleyn, B.,Fino, R.,Stoops, B.,van Vlijmen, H.,Patrick, A.N.,Yu, X.,Wong, V.,Krosky, D.J.,Abeywickrema, P.,Ortiz-Meoz, R.F.,Mason, S.W.,Jin, Z.,Sharma, S.,Jonckers, T.H.M.
DNA-Encoded Library Screen Identifies Novel Series of Respiratory Syncytial Virus Polymerase Inhibitors.
J.Med.Chem., 68:6407-6430, 2025

PubMed Abstract: Respiratory syncytial virus (RSV) remains a public health burden due to unmet therapeutic needs. We recently reported the discovery of a non-nucleoside inhibitor of the RSV polymerase and characterized its binding to a novel pocket within the capping domain of the polymerase. Here, we describe our strategy to diversify the chemical matter targeting this site by screening our DNA-encoded chemical libraries, leading to the discovery of a novel and potent series of molecules that inhibits RSV polymerase's biochemical activity, as well as its viral replication in cells. Structural analysis via cryo-EM revealed novel contacts made within the capping domain binding pocket. By leveraging these structural insights for preliminary SAR exploration, we generated analogues for which potency and metabolic stability were improved more than 60- and 40-fold, respectively, over the initial hit. This work provides a path forward for further advanced SAR exploration and development of therapeutics against RSV.

PubMed: 40042938
DOI: 10.1021/acs.jmedchem.4c02906

実験手法

ELECTRON MICROSCOPY (2.72 Å)