7DPU

SARS-CoV-2 3CL protease (3CLpro) in complex with 7-O-methyl-myricetin

7DPU の概要

• エントリーDOI: 10.2210/pdb7dpu/pdb
• 分子名称: 3C-like proteinase, 7-methoxy-3,5-bis(oxidanyl)-2-[3,4,5-tris(oxidanyl)phenyl]chromen-4-one, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: sars-cov-2, 3clpro, inhibitor, complex, myricetin, viral protein
• 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: 2
• 化学式量合計: 68407.71

構造登録者

Su, H.X.,Zhao, W.F.,Xie, H.,Li, M.J.,Xu, Y.C. (登録日: 2020-12-21, 公開日: 2021-05-12, 最終更新日: 2024-10-09)

主引用文献

Su, H.,Yao, S.,Zhao, W.,Zhang, Y.,Liu, J.,Shao, Q.,Wang, Q.,Li, M.,Xie, H.,Shang, W.,Ke, C.,Feng, L.,Jiang, X.,Shen, J.,Xiao, G.,Jiang, H.,Zhang, L.,Ye, Y.,Xu, Y.
Identification of pyrogallol as a warhead in design of covalent inhibitors for the SARS-CoV-2 3CL protease.
Nat Commun, 12:3623-3623, 2021

PubMed Abstract: The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) urgently needs an effective cure. 3CL protease (3CL) is a highly conserved cysteine proteinase that is indispensable for coronavirus replication, providing an attractive target for developing broad-spectrum antiviral drugs. Here we describe the discovery of myricetin, a flavonoid found in many food sources, as a non-peptidomimetic and covalent inhibitor of the SARS-CoV-2 3CL. Crystal structures of the protease bound with myricetin and its derivatives unexpectedly revealed that the pyrogallol group worked as an electrophile to covalently modify the catalytic cysteine. Kinetic and selectivity characterization together with theoretical calculations comprehensively illustrated the covalent binding mechanism of myricetin with the protease and demonstrated that the pyrogallol can serve as an electrophile warhead. Structure-based optimization of myricetin led to the discovery of derivatives with good antiviral activity and the potential of oral administration. These results provide detailed mechanistic insights into the covalent mode of action by pyrogallol-containing natural products and a template for design of non-peptidomimetic covalent inhibitors against 3CLs, highlighting the potential of pyrogallol as an alternative warhead in design of targeted covalent ligands.

PubMed: 34131140
DOI: 10.1038/s41467-021-23751-3

実験手法

X-RAY DIFFRACTION (1.75 Å)