9IBY
Crystal structure of Zika Virus NS2B-NS3 protease in complex with compound 2
This is a non-PDB format compatible entry.
Summary for 9IBY
| Entry DOI | 10.2210/pdb9iby/pdb |
| Descriptor | Genome polyprotein, 1-[3-[[5-(4,6-dimethylpyrimidin-5-yl)pyridin-2-yl]methyl]-1-oxa-2,3$l^{4}-diazacyclopenta-2,4-dien-5-yl]-3-[3-(trifluoromethyl)phenyl]urea, ACETIC ACID, ... (4 entities in total) |
| Functional Keywords | zika virus, ns2b-ns3 protease, allosteric inhibitor, compound 1, hydrolase |
| Biological source | Zika virus More |
| Total number of polymer chains | 2 |
| Total formula weight | 49827.19 |
| Authors | Ontario, J.M.,Torrente, E. (deposition date: 2025-02-14, release date: 2025-12-03, Last modification date: 2026-02-25) |
| Primary citation | Ontoria, J.M.,Torrente, E.,Missineo, A.,Alli, C.,Graziani, R.,Conti, S.,Bisbocci, M.,Quotadamo, A.,Ferrigno, F.,Corio, A.,Ievoli, G.,Bencheva, L.,Amaudrut, J.,Vasile, S.,Beghetto, E.,Paolini, C.,Alaimo, N.,Veneziano, M.,Nibbio, M.,Orsale, M.V.,Proto, G.,Colaceci, F.,Orsatti, L.,Pucci, V.,Di Fabio, R.,Tomei, L.,Montalbetti, C.,Bresciani, A.,Toniatti, C.,Paonessa, G. An allosteric inhibitor of the Zika virus NS2B-NS3 protease with oral efficacy in mouse models. Nat Commun, 17:1439-1439, 2026 Cited by PubMed Abstract: The mosquito-transmitted Zika virus (ZIKV) poses a global health threat, with no approved antiviral drugs or vaccines currently available. Here, we report the discovery of a series of ZIKV NS3 protease inhibitors identified through phenotypic high-throughput screening (HTS) using a ZIKV replicon-based cellular assay, and the subsequent selection of resistant mutants. These inhibitors, characterized by the presence of an N-acylsydnone imine group, bind to a previously undescribed allosteric pocket of the protease, locking the enzyme into a catalytically inactive conformation. We describe the characterization of IRBM-Z-1, our initial allosteric hit and IRBM-Z-2, a potent inhibitor of ZIKV infectivity and other orthoflavivirus proteases with a favourable in vitro and in vivo ADME profile, resulting in oral efficacy against ZIKV infection in mouse models, with potential as a prophylactic agent for human use. PubMed: 41667483DOI: 10.1038/s41467-026-68943-x PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.291 Å) |
Structure validation
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