Structural Elucidation and Antiviral Activity of Covalent Cathepsin L Inhibitors.

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 K_i range. We show a relevant off-target effect of CatL inhibition by the coronavirus m

SUBMITTER: Falke S 

PROVIDER: S-EPMC11089505 | biostudies-literature | 2024 May

REPOSITORIES: biostudies-literature