6WTT

Crystals Structure of the SARS-CoV-2 (COVID-19) main protease with inhibitor GC-376

6WTT の概要

• エントリーDOI: 10.2210/pdb6wtt/pdb
• 分子名称: 3C-like proteinase, (1S,2S)-2-({N-[(benzyloxy)carbonyl]-L-leucyl}amino)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonic acid, DI(HYDROXYETHYL)ETHER, ... (8 entities in total)
• 機能のキーワード: covid covid19 covid-19 sars sars cov2 cov ncov 19 coronavirus main protease 3cl mpro pro, viral protein, gc376, gc-376, peptidomimetic, protease, cysteine
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 105018.09

構造登録者

Sacco, M.,Ma, C.,Chen, Y.,Wang, J. (登録日: 2020-05-03, 公開日: 2020-05-20, 最終更新日: 2024-11-13)

主引用文献

Ma, C.,Sacco, M.D.,Hurst, B.,Townsend, J.A.,Hu, Y.,Szeto, T.,Zhang, X.,Tarbet, B.,Marty, M.T.,Chen, Y.,Wang, J.
Boceprevir, GC-376, and calpain inhibitors II, XII inhibit SARS-CoV-2 viral replication by targeting the viral main protease.
Cell Res., 30:678-692, 2020

PubMed Abstract: A new coronavirus SARS-CoV-2, also called novel coronavirus 2019 (2019-nCoV), started to circulate among humans around December 2019, and it is now widespread as a global pandemic. The disease caused by SARS-CoV-2 virus is called COVID-19, which is highly contagious and has an overall mortality rate of 6.35% as of May 26, 2020. There is no vaccine or antiviral available for SARS-CoV-2. In this study, we report our discovery of inhibitors targeting the SARS-CoV-2 main protease (M). Using the FRET-based enzymatic assay, several inhibitors including boceprevir, GC-376, and calpain inhibitors II, and XII were identified to have potent activity with single-digit to submicromolar IC values in the enzymatic assay. The mechanism of action of the hits was further characterized using enzyme kinetic studies, thermal shift binding assays, and native mass spectrometry. Significantly, four compounds (boceprevir, GC-376, calpain inhibitors II and XII) inhibit SARS-CoV-2 viral replication in cell culture with EC values ranging from 0.49 to 3.37 µM. Notably, boceprevir, calpain inhibitors II and XII represent novel chemotypes that are distinct from known substrate-based peptidomimetic M inhibitors. A complex crystal structure of SARS-CoV-2 M with GC-376, determined at 2.15 Å resolution with three protomers per asymmetric unit, revealed two unique binding configurations, shedding light on the molecular interactions and protein conformational flexibility underlying substrate and inhibitor binding by M. Overall, the compounds identified herein provide promising starting points for the further development of SARS-CoV-2 therapeutics.

PubMed: 32541865
DOI: 10.1038/s41422-020-0356-z

実験手法

X-RAY DIFFRACTION (2.15 Å)