9D2K

SARS-CoV-2 Papain-like Protease (PLpro) complex with covalent inhibitor Jun13567

これはPDB形式変換不可エントリーです。

9D2K の概要

• エントリーDOI: 10.2210/pdb9d2k/pdb
• 分子名称: Papain-like protease nsp3, 2-(3-{2-[4-(3,3-dimethylazetidin-1-yl)-4-oxobutanoyl]hydrazin-1-yl}-3-oxopropyl)-N-{(1R)-1-[(3P,5P)-3-(1-ethyl-1H-pyrazol-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenyl]ethyl}benzamide, 2,3-DIHYDROXY-1,4-DITHIOBUTANE, ... (6 entities in total)
• 機能のキーワード: sars cov-2, papain-like protease (plpro), covalent inhibitor, jun13567, viral protein, hydrolase-inhibitor complex, hydrolase/inhibitor
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, 2019-nCoV, COVID-19 virus)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 74320.51

構造登録者

Ansari, A.,Tan, B.,Ruiz, F.X.,Arnold, E.,Wang, J. (登録日: 2024-08-08, 公開日: 2025-03-26)

主引用文献

Tan, B.,Liang, X.,Ansari, A.,Jadhav, P.,Tan, H.,Li, K.,Ruiz, F.X.,Arnold, E.,Deng, X.,Wang, J.
Structure-Based Design of Covalent SARS-CoV-2 Papain-like Protease Inhibitors.
J.Med.Chem., 67:20399-20420, 2024

PubMed Abstract: The COVID-19 pandemic is caused by SARS-CoV-2, a highly transmissible and pathogenic RNA betacoronavirus. Like other RNA viruses, SARS-CoV-2 continues to evolve with or without drug selection pressure, and many variants have emerged since the beginning of the pandemic. The papain-like protease, PL, is a cysteine protease that cleaves viral polyproteins as well as ubiquitin and ISG15 modifications from host proteins. Leveraging our recently discovered Val70 binding site in PL, we designed covalent PL inhibitors by connecting cysteine reactive warheads to the biarylphenyl PL inhibitors via flexible linkers. Several leads displayed potent enzymatic inhibition (IC = 0.1-0.3 μM) and antiviral activity (EC = 0.09-0.96 μM). Fumaramide inhibitors , , and showed favorable pharmacokinetic properties with intraperitoneal injection. The X-ray crystal structure of PL with validated our design strategy, revealing covalent conjugation between the catalytic Cys111 and the fumaramide warhead. The results suggest these covalent PL inhibitors are promising SARS-CoV-2 antiviral drug candidates.

PubMed: 39499574
DOI: 10.1021/acs.jmedchem.4c01872

実験手法

X-RAY DIFFRACTION (2.7 Å)