8RS7

Crystal structure of Zika Virus NS2B-NS3 protease in complex with an allosteric inhibitor

This is a non-PDB format compatible entry.

Summary for 8RS7

• Entry DOI: 10.2210/pdb8rs7/pdb
• Descriptor: Genome polyprotein, 1-[3-[[5-[4-[2-(dimethylamino)ethoxy]-6-methyl-pyrimidin-5-yl]pyridin-2-yl]methyl]-1,2,3-oxadiazol-3-ium-5-yl]-3-[3-(trifluoromethyl)phenyl]urea (3 entities in total)
• Functional Keywords: zika virus, ns2b-ns3 protease, allosteric inhibitor, compound 39, hydrolase
• Biological source: Zika virus
• Total number of polymer chains: 2
• Total formula weight: 49553.26

Authors

Ontoria, J.M.,Torrente, E. (deposition date: 2024-01-24, release date: 2025-11-05, Last modification date: 2026-06-17)

Primary citation

Torrente, E.,Quotadamo, A.,Corio, A.,Ferrigno, F.,Ievoli, G.,Montalbetti, C.,Vasile, S.,Graziani, R.,Paonessa, G.,Alli, C.,Bisbocci, M.,Veneziano, M.,Proto, G.,Orsale, M.V.,di Marco, A.,Toniatti, C.,Ontoria, J.M.
Discovery and Optimization of IRBM-Z-2, an Allosteric Zika Virus NS2B-NS3 Protease Inhibitor Exhibiting In Vivo Efficacy.
J.Med.Chem., 69:13492-13503, 2026

PubMed Abstract: Zika virus is an increasing medical and socio-economic burden in (sub)tropical regions, with no effective treatments available. Previously, we identified a novel series of -carbamoylsydnone imine derivatives as potent ZIKV NS2B-NS3 protease inhibitors through phenotypic antiviral screening. Here, we report the optimization of this series, leading to , a nanomolar inhibitor active in both biochemical and cellular assays, exhibiting no cytotoxicity. demonstrates favorable oral bioavailability, low clearance, and strong prophylactic efficacy in mouse models of ZIKV infection. These results highlight as a promising therapeutic candidate against ZIKV and a potential foundation for developing broad-spectrum orthoflavirus agents.

PubMed: 42213869
DOI: 10.1021/acs.jmedchem.6c00476

Experimental method

X-RAY DIFFRACTION (3.18 Å)