7DPU

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

Summary for 7DPU

• Entry DOI: 10.2210/pdb7dpu/pdb
• Descriptor: 3C-like proteinase, 7-methoxy-3,5-bis(oxidanyl)-2-[3,4,5-tris(oxidanyl)phenyl]chromen-4-one, GLYCEROL, ... (4 entities in total)
• Functional Keywords: sars-cov-2, 3clpro, inhibitor, complex, myricetin, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV)
• Total number of polymer chains: 2
• Total formula weight: 68407.71

Authors

Su, H.X.,Zhao, W.F.,Xie, H.,Li, M.J.,Xu, Y.C. (deposition date: 2020-12-21, release date: 2021-05-12, Last modification date: 2024-10-09)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.75 Å)