TY  - JOUR
AU  - Falke, Sven
AU  - Lieske, Julia
AU  - Herrmann, Alexander
AU  - Loboda, Jure
AU  - Karničar, Katarina
AU  - Guenther, Sebastian
AU  - Reinke, Patrick
AU  - Ewert, Wiebke
AU  - Usenik, Aleksandra
AU  - Lindič, Nataša
AU  - Sekirnik, Andreja
AU  - Dretnik, Klemen
AU  - Tsuge, Hideaki
AU  - Turk, Vito
AU  - Chapman, Henry N.
AU  - Hinrichs, Winfried
AU  - Ebert, Gregor
AU  - Turk, Dušan
AU  - Meents, Alke
TI  - Structural elucidation and antiviral activity of covalent cathepsin L inhibitors
JO  - Journal of medicinal chemistry
VL  - 67
IS  - 9
SN  - 0022-2623
CY  - Washington, DC
PB  - ACS
M1  - PUBDB-2024-00424
SP  - 7048-7067
PY  - 2024
N1  - L:MB
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:38630165
UR  - <Go to ISI:>//WOS:001204960900001
DO  - DOI:10.1021/acs.jmedchem.3c02351
UR  - https://bib-pubdb1.desy.de/record/601934
ER  -