8UUW

SARS-CoV-2 papain-like protease (PLpro) with inhibitor Jun12145

8UUW の概要

• エントリーDOI: 10.2210/pdb8uuw/pdb
• 分子名称: Papain-like protease nsp3, 5-[2-(dimethylamino)ethoxy]-2-methyl-N-{(1R)-1-[(3P,5M)-3-(1-methyl-1H-pyrazol-4-yl)-5-(1,3-thiazol-5-yl)phenyl]ethyl}benzamide, DIMETHYL SULFOXIDE, ... (7 entities in total)
• 機能のキーワード: sars cov-2 papain like protease (plpro), complex, inhibitor, jun 12145, 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: 37003.97

構造登録者

Ansari, A.,Tan, B.,Ruiz, F.X.,Arnold, E.,Wang, J. (登録日: 2023-11-02, 公開日: 2024-04-03, 最終更新日: 2024-05-01)

主引用文献

Tan, B.,Zhang, X.,Ansari, A.,Jadhav, P.,Tan, H.,Li, K.,Chopra, A.,Ford, A.,Chi, X.,Ruiz, F.X.,Arnold, E.,Deng, X.,Wang, J.
Design of a SARS-CoV-2 papain-like protease inhibitor with antiviral efficacy in a mouse model.
Science, 383:1434-1440, 2024

PubMed Abstract: The emergence of SARS-CoV-2 variants and drug-resistant mutants calls for additional oral antivirals. The SARS-CoV-2 papain-like protease (PL) is a promising but challenging drug target. We designed and synthesized 85 noncovalent PL inhibitors that bind to a recently discovered ubiquitin binding site and the known BL2 groove pocket near the S4 subsite. Leads inhibited PL with the inhibitory constant K values from 13.2 to 88.2 nanomolar. The co-crystal structures of PL with eight leads revealed their interaction modes. The in vivo lead Jun12682 inhibited SARS-CoV-2 and its variants, including nirmatrelvir-resistant strains with EC from 0.44 to 2.02 micromolar. Oral treatment with Jun12682 improved survival and reduced lung viral loads and lesions in a SARS-CoV-2 infection mouse model, suggesting that PL inhibitors are promising oral SARS-CoV-2 antiviral candidates.

PubMed: 38547259
DOI: 10.1126/science.adm9724

実験手法

X-RAY DIFFRACTION (3.2 Å)