%0 Journal Article
%T Structural Elucidation and Antiviral Activity of Covalent Cathepsin L Inhibitors.
%A Falke S
%A Lieske J
%A Herrmann A
%A Loboda J
%A Karničar K
%A Günther S
%A Reinke PYA
%A Ewert W
%A Usenik A
%A Lindič N
%A Sekirnik A
%A Dretnik K
%A Tsuge H
%A Turk V
%A Chapman HN
%A Hinrichs W
%A Ebert G
%A Turk D
%A Meents A
%J J Med Chem
%V 67
%N 9
%D 2024 May 9
%M 38630165
%F 8.039
%R 10.1021/acs.jmedchem.3c02351
%X 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 EC50 range in Vero E6 cells and inhibit CatL in the picomolar Ki 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.