7EN8

Crystal structure of SARS-CoV-2 3CLpro in complex with the non-covalent inhibitor WU-04

Summary for 7EN8

• Entry DOI: 10.2210/pdb7en8/pdb
• Descriptor: 3C-like proteinase, ~{N}-[(1~{S},2~{R})-2-[[4-bromanyl-2-(methylcarbamoyl)-6-nitro-phenyl]amino]cyclohexyl]isoquinoline-4-carboxamide, GLYCEROL, ... (4 entities in total)
• Functional Keywords: non-covalent, inhibitor, 3clpro, coronavirus, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV)
• Total number of polymer chains: 2
• Total formula weight: 68795.95

Authors

Hou, N.,Peng, C.,Hu, Q. (deposition date: 2021-04-16, release date: 2022-07-20, Last modification date: 2023-11-29)

Primary citation

Hou, N.,Shuai, L.,Zhang, L.,Xie, X.,Tang, K.,Zhu, Y.,Yu, Y.,Zhang, W.,Tan, Q.,Zhong, G.,Wen, Z.,Wang, C.,He, X.,Huo, H.,Gao, H.,Xu, Y.,Xue, J.,Peng, C.,Zou, J.,Schindewolf, C.,Menachery, V.,Su, W.,Yuan, Y.,Shen, Z.,Zhang, R.,Yuan, S.,Yu, H.,Shi, P.Y.,Bu, Z.,Huang, J.,Hu, Q.
Development of Highly Potent Noncovalent Inhibitors of SARS-CoV-2 3CLpro.
Acs Cent.Sci., 9:217-227, 2023

PubMed Abstract: The 3C-like protease (3CLpro) is an essential enzyme for the replication of SARS-CoV-2 and other coronaviruses and thus is a target for coronavirus drug discovery. Nearly all inhibitors of coronavirus 3CLpro reported so far are covalent inhibitors. Here, we report the development of specific, noncovalent inhibitors of 3CLpro. The most potent one, WU-04, effectively blocks SARS-CoV-2 replications in human cells with EC values in the 10-nM range. WU-04 also inhibits the 3CLpro of SARS-CoV and MERS-CoV with high potency, indicating that it is a pan-inhibitor of coronavirus 3CLpro. WU-04 showed anti-SARS-CoV-2 activity similar to that of PF-07321332 (Nirmatrelvir) in K18-hACE2 mice when the same dose was administered orally. Thus, WU-04 is a promising drug candidate for coronavirus treatment.

PubMed: 36844503
DOI: 10.1021/acscentsci.2c01359

Experimental method

X-RAY DIFFRACTION (1.83 Å)