8YLS

Structure of SARS-CoV-2 Mpro in complex with its degrader

This is a non-PDB format compatible entry.

Summary for 8YLS

• Entry DOI: 10.2210/pdb8yls/pdb
• Descriptor: 3C-like proteinase nsp5, (4-methoxyphenyl)methyl ~{N}-[(2~{S})-4-methyl-1-oxidanylidene-1-[[(2~{S})-1-oxidanylidene-3-[(3~{S})-2-oxidanylidenepyrrolidin-3-yl]propan-2-yl]amino]pentan-2-yl]carbamate (3 entities in total)
• Functional Keywords: severe acute respiratory syndrome coronavirus 2, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 1
• Total formula weight: 34259.04

Authors

Feng, Y.,Li, W.,Cheng, S.H.,Li, X.B. (deposition date: 2024-03-06, release date: 2024-09-04, Last modification date: 2025-03-19)

Primary citation

Cheng, S.,Feng, Y.,Li, W.,Liu, T.,Lv, X.,Tong, X.,Xi, G.,Ye, X.,Li, X.
Development of novel antivrial agents that induce the degradation of the main protease of human-infecting coronaviruses.
Eur.J.Med.Chem., 275:116629-116629, 2024

PubMed Abstract: The family of human-infecting coronaviruses (HCoVs) poses a serious threat to global health and includes several highly pathogenic strains that cause severe respiratory illnesses. It is essential that we develop effective broad-spectrum anti-HCoV agents to prepare for future outbreaks. In this study, we used PROteolysis TArgeting Chimera (PROTAC) technology focused on degradation of the HCoV main protease (M), a conserved enzyme essential for viral replication and pathogenicity. By adapting the M inhibitor GC376, we produced two novel PROTACs, P2 and P3, which showed relatively broad-spectrum activity against the human-infecting CoVs HCoV-229E, HCoV-OC43, and SARS-CoV-2. The concentrations of these PROTACs that reduced virus replication by 50 % ranged from 0.71 to 4.6 μM, and neither showed cytotoxicity at 100 μM. Furthermore, mechanistic binding studies demonstrated that P2 and P3 effectively targeted HCoV-229E, HCoV-OC43, and SARS-CoV-2 by degrading M within cells in vitro. This study highlights the potential of PROTAC technology in the development of broad-spectrum anti-HCoVs agents, presenting a novel approach for dealing with future viral outbreaks, particularly those stemming from CoVs.

PubMed: 38941718
DOI: 10.1016/j.ejmech.2024.116629

Experimental method

X-RAY DIFFRACTION (1.93 Å)