7OC2

Crystal Structure of Unlinked NS2B-NS3 Protease from Zika Virus in Complex with Inhibitor MI-2295

7OC2 の概要

• エントリーDOI: 10.2210/pdb7oc2/pdb
• 分子名称: Serine protease subunit NS2B, Serine protease NS3, Cyclic 1[2-CHLORO-4-METHOXY-PHENYL-OXYMETHYL]-4-[2,6-DICHLORO-PHENYL-OXYMETHYL]-BENZENE-(7-3)-7-BENZYL-1,3-DIMETHYL-8-PIPERAZIN-1-YL-3,7-DIHYDRO-PURINE-2,6-DIONE-(7-19)-N-ACETYL-L-CYSTEINE-(8-25)-[3R-[3A,4A,5B(S*)]]-5-(1-CARBOXY-1-PHOSPHONOETHOXY)-4-HYDROXY-3-(PHOSPHONOOXY)-1-CYCLOHEXENE-1-CARBOXYLIC ACID-()-(6E,11E)-HEPTADECA-6,11-DIENE-9,9-DIYLBIS(PHOSPHONIC ACID), ... (4 entities in total)
• 機能のキーワード: flavivirin, serine protease, viral protein, ns2b-ns3, zika virus
• 由来する生物種: Zika virus (ZIKV); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 25609.90

構造登録者

Huber, S.,Heine, A.,Steinmetzer, T. (登録日: 2021-04-25, 公開日: 2022-04-06, 最終更新日: 2024-01-31)

主引用文献

Huber, S.,Braun, N.J.,Schmacke, L.C.,Quek, J.P.,Murra, R.,Bender, D.,Hildt, E.,Luo, D.,Heine, A.,Steinmetzer, T.
Structure-Based Optimization and Characterization of Macrocyclic Zika Virus NS2B-NS3 Protease Inhibitors.
J.Med.Chem., 65:6555-6572, 2022

PubMed Abstract: Zika virus (ZIKV) is a human pathogenic arbovirus. So far, neither a specific treatment nor a vaccination against ZIKV infections has been approved. Starting from our previously described lead structure, a series of 29 new macrocyclic inhibitors of the Zika virus protease containing different linker motifs have been synthesized. By selecting hydrophobic d-amino acids as part of the linker, numerous inhibitors with values < 5 nM were obtained. For 12 inhibitors, crystal structures in complex with the ZIKV protease up to 1.30 Å resolution were determined, which contribute to the understanding of the observed structure-activity relationship (SAR). In immunofluorescence assays, an antiviral effect was observed for compound containing a d-homocyclohexylalanine residue in its linker segment. Due to its excellent selectivity profile and low cytotoxicity, this inhibitor scaffold could be a suitable starting point for the development of peptidic drugs against the Zika virus and related flaviviruses.

PubMed: 35475620
DOI: 10.1021/acs.jmedchem.1c01860

実験手法

X-RAY DIFFRACTION (1.5 Å)