7QKD

Crystal structure of human Cathepsin L in complex with covalently bound MG132

Summary for 7QKD

• Entry DOI: 10.2210/pdb7qkd/pdb
• Related: 7QKB 7QKC
• Related PRD ID: PRD_001210
• Descriptor: Cathepsin L, N-[(benzyloxy)carbonyl]-L-leucyl-N-[(2S)-1-hydroxy-4-methylpentan-2-yl]-L-leucinamide, DI(HYDROXYETHYL)ETHER, ... (5 entities in total)
• Functional Keywords: cathepsin, cystein protease, drug development, drug target, peptide-like inhibitor, lysosome, protein degradation, sars-cov-2, covid-19, spike protein maturation, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 99359.14

Authors

Reinke, P.Y.A.,Falke, S.,Lieske, J.,Ewert, W.,Loboda, J.,Rahmani Mashhour, A.,Hauser, M.,Karnicar, K.,Usenik, A.,Lindic, N.,Lach, M.,Boehler, H.,Beck, T.,Cox, R.,Chapman, H.N.,Hinrichs, W.,Turk, D.,Guenther, S.,Meents, A. (deposition date: 2021-12-17, release date: 2022-12-28, Last modification date: 2024-05-15)

Primary citation

Falke, 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., 2024

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

Experimental method

X-RAY DIFFRACTION (1.5 Å)