Journal Article

PUBDB-2024-00424

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Structural elucidation and antiviral activity of covalent cathepsin L inhibitors

Falke, S. (Corresponding author)CFEL*EMBL*DESY* ; Lieske, J.CFEL*XFEL.EU*DESY* ; Herrmann, A. ; Loboda, J. ; Karničar, K. ; Guenther, S.CFEL*XFEL.EU*DESY* ; Reinke, P.CFEL*DESY* ; Ewert, W.CFEL*EMBL*DESY* ; Usenik, A. ; Lindič, N. ; Sekirnik, A. ; Dretnik, K. ; Tsuge, H. ; Turk, V. ; Chapman, H. N.CFEL*XFEL.EU*DESY* ; Hinrichs, W. ; Ebert, G. ; Turk, D. (Corresponding author) ; Meents, A. (Corresponding author)CFEL*XFEL.EU*DESY*

2024
ACS Washington, DC

This record in other databases:        

Please use a persistent id in citations: doi:10.1021/acs.jmedchem.3c02351  doi:10.3204/PUBDB-2024-00424

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.

Note: L:MB

---

Contributing Institute(s):

1. FS-CFEL-1 Fachgruppe BMX (FS-CFEL-1-BMX)
2. CFEL-Coherent X-Ray Imaging (FS-CFEL-1)

Research Program(s):

1. 633 - Life Sciences – Building Blocks of Life: Structure and Function (POF4-633) (POF4-633)
2. 6G3 - PETRA III (DESY) (POF4-6G3) (POF4-6G3)
3. FISCOV - FISCOV Helmholtz large research infrastructures in the fight against epidemic outbreaks (FISCOV) (FISCOV)
4. InternLabs-0011 - HIR3X - Helmholtz International Laboratory on Reliability, Repetition, Results at the most advanced X-ray Sources (2020_InternLabs-0011) (2020_InternLabs-0011)
5. DFG project G:(GEPRIS)527691801 - Allgemeine Aufgaben des TRR 353 (Z) (527691801) (527691801)

Experiment(s):

1. PETRA Beamline P11 (PETRA III)

Appears in the scientific report 2024

---

Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Chemical Reactions ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; Index Chemicus ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

---