6MO2

Structure of dengue virus protease with an allosteric Inhibitor that blocks replication

Summary for 6MO2

• Entry DOI: 10.2210/pdb6mo2/pdb
• Descriptor: FLAVIVIRUS_NS2B/Peptidase S7, 1-(4-{5-[(piperidin-4-yl)methoxy]-3-[4-(1H-pyrazol-4-yl)phenyl]pyrazin-2-yl}phenyl)methanamine (2 entities in total)
• Functional Keywords: allosteric inhibitor, inhibitor, complex, protease, viral protein, viral protein-inhibitor complex, viral protein/inhibitor
• Biological source: Dengue virus 2; More
• Total number of polymer chains: 2
• Total formula weight: 53542.07

Authors

Lin, Y.-L.,Nie, S.,Hua, Y.,Wu, J.,Wu, F.,Huo, T.,Yao, Y.,Song, Y. (deposition date: 2018-10-03, release date: 2019-05-15, Last modification date: 2023-10-11)

Primary citation

Yao, Y.,Huo, T.,Lin, Y.L.,Nie, S.,Wu, F.,Hua, Y.,Wu, J.,Kneubehl, A.R.,Vogt, M.B.,Rico-Hesse, R.,Song, Y.
Discovery, X-ray Crystallography and Antiviral Activity of Allosteric Inhibitors of Flavivirus NS2B-NS3 Protease.
J.Am.Chem.Soc., 141:6832-6836, 2019

PubMed Abstract: Flaviviruses, including dengue, West Nile and recently emerged Zika virus, are important human pathogens, but there are no drugs to prevent or treat these viral infections. The highly conserved Flavivirus NS2B-NS3 protease is essential for viral replication and therefore a drug target. Compound screening followed by medicinal chemistry yielded a series of drug-like, broadly active inhibitors of Flavivirus proteases with IC as low as 120 nM. The inhibitor exhibited significant antiviral activities in cells (EC: 300-600 nM) and in a mouse model of Zika virus infection. X-ray studies reveal that the inhibitors bind to an allosteric, mostly hydrophobic pocket of dengue NS3 and hold the protease in an open, catalytically inactive conformation. The inhibitors and their binding structures would be useful for rational drug development targeting Zika, dengue and other Flaviviruses.

PubMed: 31017399
DOI: 10.1021/jacs.9b02505

Experimental method

X-RAY DIFFRACTION (2.8 Å)