9OUC

Influenza A Virus Nucleoprotein(8-498)NP complex with 5-(4-(morpholinomethyl)phenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide (Compound 3)

これはPDB形式変換不可エントリーです。

9OUC の概要

• エントリーDOI: 10.2210/pdb9ouc/pdb
• 分子名称: Nucleoprotein, 5-{4-[(morpholin-4-yl)methyl]phenyl}-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide, MAGNESIUM ION, ... (4 entities in total)
• 機能のキーワード: nucleocapsid protein nucleoprotein, viral protein
• 由来する生物種: Influenza A virus (A/(Puerto Rico/8/1934-Korea/426/1968)(H2N2))
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 113869.02

構造登録者

Mamo, M. (登録日: 2025-05-28, 公開日: 2025-08-06, 最終更新日: 2025-08-20)

主引用文献

Taft, B.R.,Hesse, M.J.,Mamo, M.,Bussiere, D.E.,Huang, R.,Lee, P.S.,Wedel, L.,Growcott, E.,Wolff, K.C.,Kuhen, K.,Abend, J.,Wong, K.A.,Ganem, D.,Leonard, V.H.J.,Tully, D.C.
Discovery and Optimization of a Novel Series of Influenza A Virus Replication Inhibitors Targeting the Nucleoprotein Protein-Protein Interaction.
J.Med.Chem., 68:16349-16370, 2025

PubMed Abstract: Influenza A virus (IAV) is a negative-sense, single-stranded RNA virus that causes seasonal epidemic respiratory infections, with novel subtypes of IAV historically able to lead to pandemics that spread on a global scale. We conducted a phenotypic high-throughput screen (HTS) that identified compound as a singleton hit. Resistant viral mutants generated against analog revealed mutations in the nucleoprotein (NP). An X-ray cocrystal structure of NP in complex with compound helped define the novel mechanism of action as disruption of the NP-NP protein-protein interaction (PPI), leading to inhibition of NP oligomerization and blocking viral replication. Medicinal chemistry optimization efforts resulted in the identification of compound (VNT-101) as a potent IAV inhibitor with low nM activity across multiple subtypes. Compound has attractive DMPK and physicochemical properties, and demonstrated robust antiviral activity in rodent models of influenza infection, leading to successful completion of IND-enabling safety studies.

PubMed: 40700440
DOI: 10.1021/acs.jmedchem.5c01233

実験手法

X-RAY DIFFRACTION (2.732 Å)