Peptidomimetic α,β-Unsaturated Ethyl Esters Are Irreversible Inactivators of Human Cathepsin L and Are Potent Inhibitors of SARS-CoV-2 in Cellular Models of COVID-19
< 156 nM) and showed partial efficacy in a murine COVID-19 model. Native mass spectrometry and dilution assays confirmed irreversible hCatL inactivation. Notably, these enoates acted as reversible inhibitors of the homologue cathepsin B (hCatB). Molecular modeling suggests that hCatL's active-site cysteine is better positioned for nucleophilic addition to the vinyl group than hCatB's.
Authors
- Balachandra Chenna (ORCID: https://orcid.org/0000-0002-2660-5302)
- Aleksandra Drelich (ORCID: https://orcid.org/0000-0002-0201-5017)
- Arthur D. Laganowsky (ORCID: https://orcid.org/0000-0001-5012-5547)
- Thomas D. Meek (ORCID: https://orcid.org/0000-0002-1931-8073)
- Panatda Saenkham-Huntsinger (ORCID: https://orcid.org/0000-0001-9598-7255)
- Andrew Rademacher (ORCID: https://orcid.org/0000-0002-7041-0625)
- Chien‐Te K. Tseng (ORCID: https://orcid.org/0000-0001-5726-9834)
- Vivek Kumar (ORCID: https://orcid.org/0000-0002-7135-8398)
- Elena Scott
- Alexandria M. Kemp
Institutions
- The University of Texas Medical Branch at Galveston (US)
- Texas A&M University (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-04-21
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c03172
- Primary Topic
- Protease and Inhibitor Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.00