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Engaging a Non-catalytic Cysteine Residue Drives Potent and Selective Inhibition of Caspase-6

Authors :
Kurt S. Van Horn
Dongju Wang
Daniel Medina-Cleghorn
Peter S. Lee
Clifford Bryant
Chad Altobelli
Priyadarshini Jaishankar
Kevin K. Leung
Raymond A. Ng
Andrew J. Ambrose
Yinyan Tang
Michelle R. Arkin
Adam R. Renslo
Source :
Journal of the American Chemical Society, vol 145, iss 18
Publication Year :
2023
Publisher :
American Chemical Society (ACS), 2023.

Abstract

Caspases are a family of cysteine-dependent proteases with important cellular functions in inflammation and apoptosis, while also implicated in human diseases. Classical chemical tools to study caspase functions lack selectivity for specific caspase family members due to highly conserved active sites and catalytic machinery. To overcome this limitation, we targeted a non-catalytic cysteine residue (C264) unique to caspase-6 (C6), an enigmatic and understudied caspase isoform. Starting from disulfide ligands identified in a cysteine trapping screen, we used a structure-informed covalent ligand design to produce potent, irreversible inhibitors (3a) and chemoproteomic probes (13-t) of C6 that exhibit unprecedented selectivity over other caspase family members and high proteome selectivity. This approach and the new tools described will enable rigorous interrogation of the role of caspase-6 in developmental biology and in inflammatory and neurodegenerative diseases.

Details

ISSN :
15205126 and 00027863
Volume :
145
Database :
OpenAIRE
Journal :
Journal of the American Chemical Society
Accession number :
edsair.doi.dedup.....d2313ac4d40ba23573c730af3ed6f119
Full Text :
https://doi.org/10.1021/jacs.2c12240