Structural Elucidation and Antiviral Activity of Covalent Cathepsin L Inhibitors
Sven Falke, J. Lieske, Alexander Herrmann, Jure Loboda, Katarina Karničar, Sebastian Günther, P. Reinke, Wiebke Ewert, Aleksandra Usenik, Nataša Lindič, Andreja Sekirnik, Klemen Dretnik, Hideaki Tsuge, Vito Türk, Henry N. Chapman, Winfried Hinrichs, Gregor Ebert, Dušan Turk, Alke Meents
Abstract
High Resolution Image Download MS PowerPoint Slide 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 50 range in Vero E6 cells and inhibit CatL in the picomolar K i 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.