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8C77

Human cathepsin L after reaction with the thiocarbazate inhibitor CID 16725315

Summary for 8C77
Entry DOI10.2210/pdb8c77/pdb
Related7QKD
DescriptorCathepsin L, ~{tert}-butyl ~{N}-[(2~{S})-3-(1~{H}-indol-3-yl)-1-(2-methanoylhydrazinyl)-1-oxidanylidene-propan-2-yl]carbamate, 1,2-ETHANEDIOL, ... (9 entities in total)
Functional Keywordscystein protease, drug target, lysosome, virus cell entry, hydrolase
Biological sourceHomo sapiens (human)
Total number of polymer chains4
Total formula weight100340.01
Authors
Falke, S.,Lieske, J.,Guenther, S.,Reinke, P.Y.A.,Ewert, W.,Loboda, J.,Karnicar, K.,Usenik, A.,Lindic, N.,Sekirnik, A.,Chapman, H.N.,Hinrichs, W.,Turk, D.,Meents, A. (deposition date: 2023-01-12, release date: 2023-01-25, Last modification date: 2024-10-23)
Primary citationFalke, S.,Lieske, J.,Herrmann, A.,Loboda, J.,Karnicar, K.,Gunther, S.,Reinke, P.Y.A.,Ewert, W.,Usenik, A.,Lindic, N.,Sekirnik, A.,Dretnik, K.,Tsuge, H.,Turk, V.,Chapman, H.N.,Hinrichs, W.,Ebert, G.,Turk, D.,Meents, A.
Structural Elucidation and Antiviral Activity of Covalent Cathepsin L Inhibitors.
J.Med.Chem., 67:7048-7067, 2024
Cited by
PubMed Abstract: Emerging RNA viruses, including SARS-CoV-2, continue to be a major threat. Cell entry of SARS-CoV-2 particles via the endosomal pathway involves cysteine cathepsins. Due to ubiquitous expression, cathepsin L (CatL) is considered a promising drug target in the context of different viral and lysosome-related diseases. We characterized the anti-SARS-CoV-2 activity of a set of carbonyl- and succinyl epoxide-based inhibitors, which were previously identified as inhibitors of cathepsins or related cysteine proteases. Calpain inhibitor XII, MG-101, and CatL inhibitor IV possess antiviral activity in the very low nanomolar EC range in Vero E6 cells and inhibit CatL in the picomolar range. We show a relevant off-target effect of CatL inhibition by the coronavirus main protease α-ketoamide inhibitor 13b. Crystal structures of CatL in complex with 14 compounds at resolutions better than 2 Å present a solid basis for structure-guided understanding and optimization of CatL inhibitors toward protease drug development.
PubMed: 38630165
DOI: 10.1021/acs.jmedchem.3c02351
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.7 Å)
Structure validation

226707

数据于2024-10-30公开中

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