6MO2

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

6MO2 の概要

• エントリーDOI: 10.2210/pdb6mo2/pdb
• 分子名称: 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)
• 機能のキーワード: allosteric inhibitor, inhibitor, complex, protease, viral protein, viral protein-inhibitor complex, viral protein/inhibitor
• 由来する生物種: Dengue virus 2; 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 53542.07

構造登録者

Lin, Y.-L.,Nie, S.,Hua, Y.,Wu, J.,Wu, F.,Huo, T.,Yao, Y.,Song, Y. (登録日: 2018-10-03, 公開日: 2019-05-15, 最終更新日: 2023-10-11)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.8 Å)