9THJ
Crystal structure of H5N1 influenza polymerase PB2 domain in complex with compound 3
This is a non-PDB format compatible entry.
Summary for 9THJ
| Entry DOI | 10.2210/pdb9thj/pdb |
| Descriptor | Polymerase basic protein 2, (1~{R},2~{S},4~{R},5~{S},6~{S},7~{S})-7-[[5-fluoranyl-2-(5-fluoranyl-1~{H}-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-4-yl]amino]tricyclo[3.2.2.0^{2,4}]nonane-6-carboxylic acid, SULFATE ION, ... (4 entities in total) |
| Functional Keywords | transferase, influenza polymerase, cap-binding inhibitors |
| Biological source | Influenza A virus (A/duck/Shantou/4610/2003(H5N1)) More |
| Total number of polymer chains | 1 |
| Total formula weight | 18756.65 |
| Authors | |
| Primary citation | Wu, J.,Liu, Y.,Li, D.,Wang, L.,Neidhart, W.,Chen, B.,Hochstrasser, R.,Kuglstatter, A.,Gasser, R.,Qiu, H.,Shi, T.,Chao, S.K.,Gao, J.,Shen, H.C.,Tan, X. Discovery of Potent and Efficacious Influenza PB2 Inhibitors. Acs Med.Chem.Lett., 17:249-256, 2026 Cited by PubMed Abstract: In pursuit of potent, efficacious influenza inhibitors with novel mechanisms, we replaced the 7-azaindole core of the PB2 inhibitor pimodivir (VX-787/JNJ872) with a 7-fluoro-substituted indazole to mitigate CYP3A- and aldehyde oxidase-mediated metabolism by lowering lipophilicity and blocking the metabolic soft spot. We further introduced a cyclopropyl-fused ring onto the bridged bicyclo[2.2.2]-octane to retain potency while reducing glucuronidation. This design converged in compound , where the indazole scaffold and fused cyclopropyl ring acted synergistically to improve the potency and pharmacokinetic properties. In a lethal influenza mouse challenge model, compound achieved approximately a 7-fold reduction in the effective dose compared with pimodivir. It also showed significantly improved activity against selected influenza A strains versus pimodivir, highlighting its potential as a differentiated PB2 inhibitor. PubMed: 41531980DOI: 10.1021/acsmedchemlett.5c00674 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (0.91 Å) |
Structure validation
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