8C77

Human cathepsin L after reaction with the thiocarbazate inhibitor CID 16725315

8C77 の概要

• エントリーDOI: 10.2210/pdb8c77/pdb
• 関連するPDBエントリー: 7QKD
• 分子名称: Cathepsin 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)
• 機能のキーワード: cystein protease, drug target, lysosome, virus cell entry, hydrolase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 100340.01

構造登録者

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. (登録日: 2023-01-12, 公開日: 2023-01-25, 最終更新日: 2024-10-23)

主引用文献

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., 67:7048-7067, 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

実験手法

X-RAY DIFFRACTION (1.7 Å)