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)
This is a non-PDB format compatible entry.
Summary for 9OUC
| Entry DOI | 10.2210/pdb9ouc/pdb |
| Descriptor | Nucleoprotein, 5-{4-[(morpholin-4-yl)methyl]phenyl}-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxamide, MAGNESIUM ION, ... (4 entities in total) |
| Functional Keywords | nucleocapsid protein nucleoprotein, viral protein |
| Biological source | Influenza A virus (A/(Puerto Rico/8/1934-Korea/426/1968)(H2N2)) |
| Total number of polymer chains | 2 |
| Total formula weight | 113869.02 |
| Authors | |
| Primary citation | 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., 2025 Cited by 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: 40700440DOI: 10.1021/acs.jmedchem.5c01233 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.732 Å) |
Structure validation
Download full validation report
