{Reference Type}: Journal Article
{Title}: Structural Elucidation and Antiviral Activity of Covalent Cathepsin L Inhibitors.
{Author}: Falke S;Lieske J;Herrmann A;Loboda J;Karničar K;Günther S;Reinke PYA;Ewert W;Usenik A;Lindič N;Sekirnik A;Dretnik K;Tsuge H;Turk V;Chapman HN;Hinrichs W;Ebert G;Turk D;Meents A;
{Journal}: J Med Chem
{Volume}: 67
{Issue}: 9
{Year}: 2024 May 9
{Factor}: 8.039
{DOI}: 10.1021/acs.jmedchem.3c02351
{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 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.