9IBY

Crystal structure of Zika Virus NS2B-NS3 protease in complex with compound 2

これはPDB形式変換不可エントリーです。

9IBY の概要

• エントリーDOI: 10.2210/pdb9iby/pdb
• 分子名称: 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)
• 機能のキーワード: zika virus, ns2b-ns3 protease, allosteric inhibitor, compound 1, hydrolase
• 由来する生物種: Zika virus; 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 49827.19

構造登録者

Ontario, J.M.,Torrente, E. (登録日: 2025-02-14, 公開日: 2025-12-03, 最終更新日: 2026-02-25)

主引用文献

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

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: 41667483
DOI: 10.1038/s41467-026-68943-x

実験手法

X-RAY DIFFRACTION (2.291 Å)