9D2K
SARS-CoV-2 Papain-like Protease (PLpro) complex with covalent inhibitor Jun13567
This is a non-PDB format compatible entry.
Summary for 9D2K
| Entry DOI | 10.2210/pdb9d2k/pdb |
| Descriptor | Papain-like protease nsp3, 2-(3-{2-[4-(3,3-dimethylazetidin-1-yl)-4-oxobutanoyl]hydrazin-1-yl}-3-oxopropyl)-N-{(1R)-1-[(3P,5P)-3-(1-ethyl-1H-pyrazol-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenyl]ethyl}benzamide, 2,3-DIHYDROXY-1,4-DITHIOBUTANE, ... (6 entities in total) |
| Functional Keywords | sars cov-2, papain-like protease (plpro), covalent inhibitor, jun13567, viral protein, hydrolase-inhibitor complex, hydrolase/inhibitor |
| Biological source | Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, 2019-nCoV, COVID-19 virus) |
| Total number of polymer chains | 2 |
| Total formula weight | 74320.51 |
| Authors | Ansari, A.,Tan, B.,Ruiz, F.X.,Arnold, E.,Wang, J. (deposition date: 2024-08-08, release date: 2025-03-26) |
| Primary citation | Tan, B.,Liang, X.,Ansari, A.,Jadhav, P.,Tan, H.,Li, K.,Ruiz, F.X.,Arnold, E.,Deng, X.,Wang, J. Structure-Based Design of Covalent SARS-CoV-2 Papain-like Protease Inhibitors. J.Med.Chem., 67:20399-20420, 2024 Cited by PubMed Abstract: The COVID-19 pandemic is caused by SARS-CoV-2, a highly transmissible and pathogenic RNA betacoronavirus. Like other RNA viruses, SARS-CoV-2 continues to evolve with or without drug selection pressure, and many variants have emerged since the beginning of the pandemic. The papain-like protease, PL, is a cysteine protease that cleaves viral polyproteins as well as ubiquitin and ISG15 modifications from host proteins. Leveraging our recently discovered Val70 binding site in PL, we designed covalent PL inhibitors by connecting cysteine reactive warheads to the biarylphenyl PL inhibitors via flexible linkers. Several leads displayed potent enzymatic inhibition (IC = 0.1-0.3 μM) and antiviral activity (EC = 0.09-0.96 μM). Fumaramide inhibitors , , and showed favorable pharmacokinetic properties with intraperitoneal injection. The X-ray crystal structure of PL with validated our design strategy, revealing covalent conjugation between the catalytic Cys111 and the fumaramide warhead. The results suggest these covalent PL inhibitors are promising SARS-CoV-2 antiviral drug candidates. PubMed: 39499574DOI: 10.1021/acs.jmedchem.4c01872 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.7 Å) |
Structure validation
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