9DOI

SARS-CoV-2 papain-like protease (PLpro) with inhibitor Jun13306

これはPDB形式変換不可エントリーです。

9DOI の概要

• エントリーDOI: 10.2210/pdb9doi/pdb
• 分子名称: Papain-like protease nsp3, 2-methyl-N-{(1S)-1-[(2P)-2-(1-methyl-1H-pyrazol-4-yl)quinolin-4-yl]ethyl}-5-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}benzamide, DI(HYDROXYETHYL)ETHER, ... (7 entities in total)
• 機能のキーワード: sars cov-2 papain like protease (plpro), complex, inhibitor, jun13306, 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: 1
• 化学式量合計: 37096.84

構造登録者

Ansari, A.,Jadhav, P.,Arnold, E.,Ruiz, F.X.,Wang, J. (登録日: 2024-09-19, 公開日: 2025-01-22, 最終更新日: 2025-02-26)

主引用文献

Jadhav, P.,Liang, X.,Ansari, A.,Tan, B.,Tan, H.,Li, K.,Chi, X.,Ford, A.,Ruiz, F.X.,Arnold, E.,Deng, X.,Wang, J.
Design of quinoline SARS-CoV-2 papain-like protease inhibitors as oral antiviral drug candidates.
Nat Commun, 16:1604-1604, 2025

PubMed Abstract: The ever-evolving SARS-CoV-2 variants necessitate the development of additional oral antivirals. This study presents the systematic design of quinoline-containing SARS-CoV-2 papain-like protease (PL) inhibitors as potential oral antiviral drug candidates. By leveraging the recently discovered Val70 binding site in PL, we designed a series of quinoline analogs demonstrating potent PL inhibition and antiviral activity. Notably, the X-ray crystal structures of 6 lead compounds reveal that the 2-aryl substitution can occupy either the Val70 site as expected or the BL2 groove in a flipped orientation. The in vivo lead Jun13296 exhibits favorable pharmacokinetic properties and potent inhibition against SARS-CoV-2 variants and nirmatrelvir-resistant mutants. In a mouse model of SARS-CoV-2 infection, oral treatment with Jun13296 significantly improves survival, reduces body weight loss and lung viral titers, and prevents lung tissue damage. These results underscore the potential of quinoline PL inhibitors as promising oral SARS-CoV-2 antiviral candidates, instilling hope for the future of SARS-CoV-2 treatment.

PubMed: 39948104
DOI: 10.1038/s41467-025-56902-x

実験手法

X-RAY DIFFRACTION (2.3 Å)