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Falke, S.* ; Lieske, J.* ; Herrmann, A. ; Loboda, J.* ; Karničar, K.* ; Günther, S.* ; Reinke, P.Y.A.* ; Ewert, W.* ; Usenik, A.* ; Lindič, N.* ; Sekirnik, A.* ; Dretnik, K.* ; Tsuge, H.* ; Turk, V.* ; Chapman, H.N.* ; Hinrichs, W.* ; Ebert, G. ; Turk, D.* ; Meents, A.*

Structural elucidation and antiviral activity of covalent cathepsin L inhibitors.

J. Med. Chem. 67, 7048-7067 (2024)

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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 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.

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